Traditional Chinese medicine-combination therapies utilizing nanotechnology-based targeted delivery systems: a new strategy for antitumor treatment

Figures & data

Figure 1 Advantages of targeted nanotechnology-based TCM-combination therapy.

Notes: (A) Antitumor effects of TCM; (B) antitumor effects of TCM-combination therapy; (C) antitumor effects of targeted nanotechnology-based TCM-combination therapy.

Abbreviations: TCM, traditional Chinese medicine; MDR, multidrug resistance.

Table 1 Antitumor effects of traditional Chinese medicine

Monomer composition	Source (Chinese name)	Anticancer category	Anticancer property
Curcumin (C21H20O6)	Curcuma longa (jiang huang)	Breast cancer, neurological cancers, lymphoma, lung cancer, melanoma, sarcoma, leukemia, gastrointestinal cancers, ovarian cancer, genitourinary cancers^Citation14	It can inhibit the initiation step of cancer and malignant- cell proliferation during the promotion and progression of carcinogenesis.^Citation15
Arsenic trioxide (As2O3)	Arsenic (pi shuang)	Acute promyelocytic leukemia,^Citation16 renal cancer, prostate cancer, hepatocellular carcinoma,^Citation17^–^Citation19 lung cancer^Citation20,Citation21	As2O3 can induce the accumulation of cellular ROS, causing DNA damage and leading to cell-cycle arrest and apoptosis in various solid tumors.^Citation17^–^Citation19
Resveratrol (C14H12O3)	Polygonum cuspidatum (hu zhang)	Osteosarcoma cells,^Citation22 23 breast cancer, colon cancer,^Citation24 cervical cancer, blood cancer, kidney cancer, liver cancer, bladder cancer, thyroid cancer, esophageal cancer, prostate cancer, brain cancer, gastric cancer, bone cancer, ovarian cancer^Citation25	It can induce apoptosis and inhibit proliferation by modulating the PI3K–Akt–mTOR and MAPK pathways.^Citation22,Citation26,Citation27
Ginsenoside Rg3 (C42H72O13)	Panax ginseng (ren shen)	Breast cancer cells,^Citation28 colorectal tumor,^Citation29 ovarian cancer^Citation30	Ginsenoside Rg3 can inhibit tumor development by inhibiting tumor angiogenesis, regulating apoptosis of tumor cells, controlling the proliferation, invasion, and metastasis of tumor cells, and inhibiting multidrug resistance.^Citation28^–^Citation30
Baicalein (C15H10O5)	Scutellaria baicalensis (huang qin)	HCT116 human colon cancer,^Citation31 pancreatic cancer stem cells,^Citation32 bladder cancer,^Citation33 breast cancer,^Citation34 gastric cancer,^Citation35 hepatocellular carcinoma^Citation36	It can inhibit a variety of cyclins or cyclin-dependent kinases, regulate the cell cycle,^Citation37 scavenge oxidative radicals, weaken MAPK, Akt, or mTOR activities,^Citation38 inducing apoptosis^Citation39 and inhibiting the invasion and metastasis of tumors.^Citation40
Gambogic acid (C38H44O8)	Garcinia hanburyi (teng huang)	Gastric cancer,^Citation41 prostate cancer,^Citation42 lung cancer,^Citation43 pancreatic cancer,^Citation44 hepatocarcinoma^Citation45	Gambogic acid can induce apoptosis,^Citation46 enhance the accumulation of ROS,^Citation47 and inhibit telomerase activity.^Citation41,Citation43
Gambogenic acid (C38H46O9)	Garcinia hanburyi (teng huang)	Human nasopharyngeal carcinoma CNE1 cells,^Citation48 U251 glioblastoma cells,^Citation49 breast cancer,^Citation50 lung cancer^Citation51	Gambogenic acid is associated with inhibition of proliferation of A549 cells by apoptosis induction and cell-cycle arrest,^Citation48,Citation52,Citation53 and can mediate apoptosis in human nasopharyngeal carcinoma CNE1 cells.^Citation49
Quercetin (C15H10O7)	Hypericum ascyron (hong han lian)	Melanoma,^Citation54 HL60 cells^Citation57 prostate cancer,^Citation55 breast cancer,^Citation56 human leukemia	Quercetin can induce cancer-cell apoptosis by modulating signaling pathways and blocking cell-cycle progression,^Citation58 as well as actively suppress cancer proliferation and cancer metastasis.^Citation59
Triptolide (C20H24O6)	Tripterygium wilfordii (lei gong teng)	Medulloblastoma,^Citation60 lung cancer cells,^Citation61 blood cancer cells, colon cancer cells, breast cancer cells, brain cancer cells, ovary cancer cells, kidney cancer cells, prostate cancer cells^Citation62,Citation63	Triptolide can inhibit cell proliferation and arrest the cell cycle,^Citation64 increase LC3α expression levels,^Citation65 and inhibit the PI3K–Akt–mTOR pathway. While ERK1/2 is activated, autophagy of cell death is induced.^Citation66,Citation67
Berberine (C20H18NO4)	Coptis chinensis (huang lian)	Human malignant pleural mesothelioma NCIH2452 cells,^Citation68 human colon cancer cells,^Citation69 hepatocellular carcinoma,^Citation70 breast cancer cells,^Citation71,Citation72 human HSC3 oral cancer cells,^Citation73 human epidermoid carcinoma A431 cells^Citation74	It can inhibit cancer-cell proliferation, induce cell-cycle arrest at the G1/G0 phase, induce apoptosis in cancer cells,^Citation69 cause cell-growth inhibition, and suppress cell migration and invasion.^Citation71^–^Citation74
Cryptotanshinone (C19H20O3)	Salvia miltiorrhiza (dan shen)	Prostate cancer,^Citation75 breast carcinoma,^Citation76 lung cancer^Citation77	It inactivates STAT3 activity,^Citation75 arrests the cell cycle in the G1/G0 phase, and inhibits expression of cyclin D1.^Citation76
Tetramethylpyrazine (C8H12N2)	Ligusticum striatum (chuan xiong)	Lung cancer,^Citation78 osteosarcoma^Citation79	It can reduce activities of COX2 and MMP2/TIMP2,^Citation78 upregulate cytosolic NFκB p65 expression, and downregulate protein expression of nuclear NFκB p65, BCL2, and cyclin D1.^Citation79
Dihydroartemisinin (C15H24O5)	Artemisia annua (huang hua hao)	Pancreatic cancer,^Citation80 osteosarcoma,^Citation81 liver cancer,^Citation82 leukemia^Citation83,Citation84	It can activate caspase 3, caspase 8, and caspase 9, upregulate the expression of Fas, cyclin D1, and Bax, downregulate the expression of CDC25B, Bcl2, and cyclin B1, and inhibit NFκB activity.^Citation85
Ginsenoside Rh2 (C36H62O8)	Panax ginseng (ren shen)	Breast cancer,^Citation86 ovarian cancer,^Citation87 prostate cancer,^Citation88 leukemia,^Citation89 colorectal cancer,^Citation90 hepatocellular carcinoma^Citation91	Some signaling pathways, such as TNFα,^Citation92 EGFR,^Citation93 JAK–STAT3,^Citation94 and PI3K–Akt^Citation95 have been implicated in the regulatory process of Rh2 in cancer cells.
Plumbagin (C11H8O3)	Plumbago zeylanica (bai hua dan)	Prostate cancer,^Citation96 breast cancer cells,^Citation97 melanoma cells^Citation98	It can induce apoptosis and autophagy, destroy the cell cycle, inhibit invasion and metastasis, and prevent angiogenesis, with anticancer potential in different cancer cells in vitro and in vivo.^Citation99

Figure 2 Chemical structures of the active components in traditional Chinese medicine.

Table 2 Antitumor effects of TCM-combination therapy

Monomer composition	Combination therapy	Cellular, animal levels	Advantages of combination therapies	Reference
Curcumin (Cur)	Cur + cisplatin	Human non-small-cell lung cancer (NSCLC) A549, A549-xenograft mouse model	Cur can strengthen the antitumor effect of cisplatin in A549 cells in vitro. Cur combined with cisplatin can inhibit tumor growth and promote apoptosis in xenograft mouse model.	^Citation108
	Cur + paclitaxel	Breast cancer cell line MCF7, MCF7-xenograft mouse model	Cur combined with paclitaxel can inhibit the growth of MCF7 cells synergistically, induce significant apoptosis in MCF7 cell lines, and exert increased antitumor efficacy in mouse models.	^Citation117
	Cur + Rsv	Breast epithelial MCF10A-Tr, tumor xenograft in mice	Cur and Rsv causes apoptosis synergistically in breast cancer cells by p2 Waf/Cip1-mediated inhibition of Hedgehog–Gli cascade.	^Citation109
		Colon cancer HCT116 (wild type) cells, xenografts in SCID mice	The combination of Cur and Rsv has stronger inhibitory effects on the growth of p53-positive (wild type) and p53-negative (HCT116) colon cancer cells in vitro and in vivo than either agent alone.	^Citation119
	Cur + Rsv–diallyl disulfide	Malignant rhabdoid (SJRH4, RD/18) and osteosarcoma (SAOS2) cell lines	Cur induces apoptosis in rhabdomyosarcoma and osteosarcoma cells, which is potentiated when Cur is combined with Rsv or diallyl disulfide.	^Citation120
	Cur + As2O3/lonidamine	U937 and HL60 human acute myeloid leukemia cells, K562 chronic myelogenous leukemia cells	Cur plus As2O3 or lonidamine stimulates events typical of the mitochondrial executioner pathway. Cotreatment with Cur may be an effective way to improve the efficacy of As2O3 and lonidamine as antineoplastic agents for myeloid leukemia cells.	^Citation121
	Cur + vesicular stomatitis virus	PC3 prostate cancer cells, mouse model of prostate cancer	Cur makes prostate cancer cells sensitive to the oncolytic effects of vesicular stomatitis virus through modulating antiviral responses and components of the intrinsic apoptotic pathway.	^Citation122
	Cur + Qct	Human gastric cancer MGC803 cells	The combination of Cur and Qct has a significant inhibitory effect on cell proliferation and a stronger effect on gastric cancer MGC803 cells than individual therapy.	^Citation123
Arsenic trioxide (ATO)	ATO + artesunate	Human K562 cell lines	Artesunate combined with ATO can significantly promote apoptosis of K562 cells induced by artesunate.	^Citation124
	ATO + dihydroartemisinin	A549 cells	Dihydroartemisinin effectively sensitizes A549 cells to ATO, increasing the effectiveness of ATO-induced cell death, and can cooperate with ATO to exert synergistic effects in promoting apoptosis in A549 lung cancer cells.	^Citation85
	ATO + cisplatin– doxorubicin (Dox)	HepG2 cell lines, hepatic cancer stem cells	This study was critical in realizing the potential for synergy between ATO and chemotherapeutic protocols, such as cisplatin and Dox.	^Citation125
		Human hepatoma BEL7402 cells, mouse hepatoma HepA	Low-dose cisplatin or Dox and ATO in combination can increase the antihepatocarcinoma effect.	^Citation126
	ATO + Dox	SGC7901/S human GC cell line, Dox-resistant SGC7901/ADM cell line	ATO can reverse MDR to Dox in human GC cells. This may be relevant to decreased Pgp expression.	^Citation127
	ATO + matrine	Myeloma cell lines RPMI 8226 and U266	Matrine shows an antimyeloma effect by inducing apoptosis, and ATO combined with matrine enhances apoptosis induced by matrine, having synergistic effects.	^Citation128
Resveratrol (Rsv)	Rsv + cisplatin	A549 cells	Rsv combined with cisplatin synergistically induced apoptosis by modulating autophagic cell death in A549 cells.	^Citation104
	Rsv + Dox	MCF7 and MDA-MB231 cell lines, Ehrlich ascitic carcinoma–bearing mice	Rsv combined with Dox can inhibit tumor volume and prolong the life of Ehrlich ascitic carcinoma cell–bearing mice.	^Citation129
	Rsv + paclitaxel	HepG2 human liver cancer cells	Rsv can enhance the anticancer effect of paclitaxel on HepG2 cells and be used as a sensitizer of paclitaxel.	^Citation130
		NSCLC cell line A549	Rsv enhances the anticancer effects of paclitaxel in A549 cells, and thus Rsv might be used as an excellent sensitizer for paclitaxel.	^Citation131
	Rsv + temozolomide	Human glioblastoma U87 MG and GBM8401 cell lines, GBM-SKH (GBM) cell line, orthotopic xenograft model	Rsv can enhance temozolomide-mediated antitumor effects in glioblastoma multiforme in vitro and in vivo by ROS-dependent AMPK–TSC–mTOR signaling pathway.	^Citation132
	Rsv + Qct	Human hepatoblastoma HepG2 cells	Rsv plays different roles in autophagy according to cellular energy state, and can represent a promising strategy to sensitize cancer cells to Qct therapy.	^Citation133
	Rsv + As2O3	HeLa, MCF7, and NB4 cells, HeLa-cell mouse model	Rsv can significantly raise the antitumor effect induced by As2O3 in vitro, and As2O3 combined with Rsv can significantly inhibit tumor growth and angiogenesis in nude mice.	^Citation134
Ginsenoside Rg3	Rg3 + As2O3	NCIH1299 lung cancer cells, nude mice bearing hepatoma	As2O3 combined with Rg3 can dramatically inhibit proliferation of NCIH1299 cells and prolong the survival of nude mice bearing tumors, having a significant effect on lung cancer therapy.	^Citation112
	Rg3 + paclitaxel	Triple-negative breast cancer lines MDA-MB231, sMDA-MB453, BT549, mouse MDA-MB231-xenograft model	Rg3 promotes cytotoxicity and apoptotic effects of paclitaxel on triple-negative breast cancer through inhibition of NFκB activity and regulating Bax/Bcl2 expression.	^Citation113
	Rg3 + paclitaxel/cisplatin	Mouse tumor-xenograft models	The combined use of Rg3 can remarkably raise the inhibitory effects of chemotherapy on tumor growth, and expression levels of Ki67 in the chemotherapy + Rg3 group were significantly lower than in the other groups (Rg3 alone, paclitaxel alone, and cisplatin alone).	^Citation114
	Rg3 + docetaxel	Colon cancer (HCT116 and SW620) cells	Compared to treatment with Rg3 or docetaxel alone, combination therapy can inhibit the growth of cancer cells and induce apoptosis of cancer cells more effectively, accompanied by significant inhibition of NFκB activity.	^Citation135
Baicalein (BA)	BA + taxol	Human ovarian cancer A2780 cells, SKOV3 cells, and OVCAR cells	BA combined with taxol at low concentrations can play a synergistic antitumor role via the Akt–β-catenin signaling pathway and mitochondria-mediated cell apoptosis in ovarian cancer cells.	^Citation136
	BA + 10-hydroxycamptothecin (Hcpt)	BGC823, MCF7, and SMMC7721 cells, mice xenografted with BGC823 tumors	In BGC823, MCF7, and SMMC7721 cells, BA significantly enhances the anticancer activity of Hcpt at an atoxic dose. Hcpt with BA is a novel and effective combination therapy, which synergistically target Topo I and upregulate p53 to induce cell-cycle arrest and cell apoptosis.	^Citation115
Gambogic acid (GA)	GA + cisplatin	Human NSCLC A549, NCIH460, and NCIH1299 cell lines	GA synergizes the growth-inhibitory activity of CDDP and enhances the apoptosis-induced effect of CDDP on NSCLC cells, meanwhile sensitizing lung cancer cells to CDDP in vitro and in vivo.	^Citation137
	GA + gemcitabine	PANC1 and BxPC3 cells, mouse xenograft model of human pancreatic cancer	GA inhibits the activation of ERK–E2F1–RRM2 signaling pathway to sensitize pancreatic cancer cells to gemcitabine in vitro and in vivo.	^Citation138
	GA + sunitinib	Renal carcinoma cell lines 786O and CAKI1, mouse xenograft models	Therapy of 786O and CAKI1 cells with GA or sunitinib can reduce the proliferation of tumor cells, especially when combined with the two medicines. The combination of GA and sunitinib has greater antitumor efficacy than either drug alone.	^Citation139
Gambogenic acid (GNA)	GNA + adriamycin (Adr)	MCF7 cell lines, MCF7/ADR cell lines	GNA can increase the chemosensitivity of breast cancer cells to Adr. This modulatory role is mediated by suppression of the PTEN–PI3K–Akt pathway, leading to apoptosis in MCF7/ADR cells.	^Citation140
	GNA + bortezomib (Btz)	Myeloma MM1S cells, tumor-xenograft models	Btz and GNA have strong synergistic effect in combination therapy, inducing apoptosis of MM.1S cells. The combination of Btz and GNA is superior to single drug on MM.1S-xenograft models.	^Citation141
Quercetin (Qct)	Qct + tamoxifen	Prostate-tumor xenografts in mice	Tamoxifen combined with Qct can effectively delay the occurrence of tumors, inhibit the final volume of tumors, and reduce the weight of the end-point tumor (P<0.05).	^Citation142
	Qct + metformin	PC3 and LNCaP cells, prostate cancer xenografts in nude mice	Combined application of metformin and Qct has a significantly stronger effect on apoptosis of prostate cancer cells than monotherapy, and combination therapy can inhibit the VEGF–Akt–PI3K signaling pathway to play a synergistic antitumor effect.	^Citation143
	Qct + trichostatin A	Mouse xenograft model of A549 cells	Qct enhances the antitumor effect of trichostatin A and prevents trichostatin A-induced muscle wasting.	^Citation144
	Qct + Hcpt	MCF7, BGC823, and HepG2 cells, MCF7 xenograft in nude mice	The combination of Qct and Hcpt can inhibit Topo I in MCF7 cells, which synergistically induces cell-cycle arrest and apoptosis by triggering DNA damage.	^Citation145
	Qct + irinotecan–SN38	The AGS human gastric adenocarcinoma cell line, AGS xenograft mouse model	Qct combined with irinotecan has a superior regulatory effect on angiogenesis and EMT-related factors. Qct may enhance the efficacy of irinotecan–SN38 in the human AGS cell line.	^Citation146
Triptolide (TL)	TL + sorafenib	Huh7 and PLC/PRF/5 cells, Huh7 tumor-xenograft mouse model	Sorafenib combined with TL is superior to single-drug therapy in increasing cell death and apoptosis in vitro.	^Citation147
	TL + cisplatin	Human gastric adenocarcinoma SCM1 cells, xenografts in SCID mice	TL can raise the cytotoxicity of cisplatin to SCM1 cells, and the combined therapy can significantly inhibit the growth of tumors.	^Citation111
		Urothelial cancer cells, PC3 prostate cancer cell line, mouse xenograft model	Cancer-specific enhancement of cisplatin-induced cytotoxicity with TL by the interaction of inactivated GSK3β with p53.	^Citation148
	TL + oxaliplatin	Colon cancer cell line SW480, nude mouse model	Combination therapy with TL and oxaliplatin exerts synergistic antitumor effects at low concentrations in colon cancer cells, with less cytotoxicity, which exhibits high potency for clinical applications.	^Citation149
	TL + fluorouracil	Colon carcinoma HT29 cells, tumor xenografts in nude mice	The combined effects of TL and fluorouracil on the growth of colon carcinoma are better than that of single drug, whether in vitro or in vivo. TL combined with fluorouracil has synergistic effects at lower concentrations and promotes apoptosis, but the side effects of chemotherapy are not increased.	^Citation150
	TL + gemcitabine	Pancreatic cancer BxPC3 and PANC1 cell lines	TL can increase gemcitabine-induced cell-growth inhibition and apoptosis synergistically. When TL is combined with gemcitabine, the potential for therapy of pancreatic cancer increases markedly.	^Citation151
Berberine (Bbr)	Bbr + Dox	Human breast cancer MCF7/MDR cells, tumor xenografts in the BALB/c nu/nu mice	Bbr can increase the sensitivity of drug-resistant breast cancer to Dox chemotherapy and can directly induce apoptosis in vitro and in vivo by dose-orchestrated AMPK signaling.	^Citation152
		NSCLC NCIH460, NCIH1975 cells	Bbr inhibits Dox-mediated STAT3 activation and enhances the cytotoxic effect in lung cancer cells of Dox treatment.	^Citation153
	Bbr + evodiamine	Human breast cancer MCF7 cells, mice with MCF7 human breast cancer xenografts	Bbr combined with evodiamine plays a synergistic role in inhibiting the proliferation of MCF7 cells through inducing cell-cycle arrest and apoptosis.	^Citation154
	Bbr + galangin	ECA9706 cells, nude mice with xenograft tumors	Galangin combined with Bbr synergistically exerts cell-growth inhibition, apoptosis, and cell-cycle arrest in esophageal carcinoma cells and also exhibits outstanding synergistic anticancer role in vivo.	^Citation155
	Bbr + tamoxifen	MCF7 and MCF7/TAM cells	Bbr combined with tamoxifen is more effective than tamoxifen alone in inducing cell-growth inhibition, inducing G1-phase arrest and activating cell apoptosis.	^Citation156
	Bbr + sorafenib	SMMC7721 and HepG2 cells	The combination of Bbr and sorafenib exhibits a synergistic inhibitory effect on the proliferation of SMMC7721 and HepG2 cells.	^Citation157
Allicin (AN)	AN + IL2	BXPC3 cell line, pancreatic cancer xenograft in mice	The combination of AN and IL2 can inhibit the growth of tumors and prolong survival, possibly by activation of CD4^+ T, CD8^+ T, and NK cells.	^Citation158
	AN + fluorouracil	SK-Hep1 and BEL7402 cell lines, hepatocellular carcinoma-xenograft models in nude mice	By ROS-mediated mitochondrial pathway, AN can increase the sensitivity of hepatocellular carcinoma cells to fluorouracil-induced-apoptosis. Combination of AN and fluorouracil can be used as a novel chemotherapeutic regimen for hepatocellular carcinoma.	^Citation159
Dihydroberberine (Dhb)	Dhb + sunitinib	Human NSCLC NCIH460, NCIH460 cell-xenografted nude mice	Sunitinib shows synergistic effects on proliferation, colony formation, and growth of transplantable tumors of NCIH460 cells, suggesting that Dhb can increase the sensitivity of lung cancer to sunitinib.	^Citation160
Oxymatrine (Omt)	Omt + oxaliplatin	Colon cancer lines (HT29 and SW480), SW480 xenograft mouse model	A combined index value <1 for Omt and oxaliplatin has a synergistic effect. Compared with oxaliplatin or Omt alone, combination therapy has more effective inhibition on tumor weight and volume of SW480-xenotransplant mice.	^Citation161
	Omt + NM3	Human gastric cancer cell lines SGC7901, MKN45, MKN74, human gastric cancer xenografted in mice	Omt combined with NM3 can synergistically inhibit the growth of human gastric cancer cell line SGC7901 in vitro and the growth of xenograft human gastric cancer cell line SGC7901 in vivo.	^Citation162
Tetraarsenic oxide (TAO)	TAO + cisplatin	Human cervical carcinoma cell line HPV16, CaSki cells, mice bearing CaSki-cell tumors	TAO can induce apoptosis. Combined with cisplatin, it can significantly increase the number of apoptotic cells, exerting a synergistic role.	^Citation163
Cryptotanshinone (Cts)	Cts + cisplatin	A549 cells, A549/DDP cells	Compared with cisplatin monotherapy, the combination of Cts and cisplatin induces cell death and apoptosis by increasing the sensitivity of A549/DDP cells to cisplatin. Cts can reverse the resistance of human lung cancer A549 cells to cisplatin by downregulating the Nrf2 pathway.	^Citation110
Tetramethylpyrazine (Tmp)	Tmp + cisplatin (CDDP)	Lewis lung cancer mice	The inhibitory effect of Tmp combined with DDP on tumor growth is enhanced compared to Tmp- or CDDP-alone treatment. Tmp with CDDP had additional or synergistic effects to inhibit tumor growth effectively.	^Citation164
Catechin (RQC)	RQC + gefitinib	Human metastatic breast cancer cell line MDA-MB231, hairless SCID female mice	Combination of RQC and gefitinib can significantly reduce the viability of gefitinib- resistant breast cancer cells. Compared with RQC or gefitinib alone, it can significantly inhibit the growth and metastasis of breast tumors in nude mice.	^Citation165
Dihydroartemisinin (Dha)	Dha + gemcitabine	BxPC3 and PANC1 cell lines, BALB/c nude mice	Dha significantly enhances the inhibition and apoptosis of gemcitabine on BxPC3 and PANC1 cell lines in vitro. Combination therapy can significantly enhance the antitumor effect of gemcitabine.	^Citation80
Epigallocatechin- 3-gallate (EGCG)	EGCG + Dox	Human prostate-cell lines, mouse tumor modeling with PC3ML cells	EGCG can be effectively used to improve the efficacy of Adr through improving its ability to eradicate highly aggressive, metastatic, or primary tumors.	^Citation166
		Human HCC cell line BEL7404/Dox, xenograft mouse model	EGCG can enhance Dox-induced cytotoxicity and increase the sensitivity of drug-resistant hepatocellular carcinoma cells to Dox at an atoxic dose.	^Citation167
Ginsenoside Rh2	Rh2 + paclitaxel–mitoxantrone	LNCaP prostate-tumor cells, human LNCaP-tumor xenograft	Rh2 combined with paclitaxel shows stronger inhibition and synergistic effect on growth in a cultured LNCaP cell line.	^Citation88

Abbreviations: SCID, severe combined immunodeficiency; MDR, multidrug resistance; CDDP, cis-diamminedichloroplatinum; EMT, epithelial–mesenchymal transition.

Figure 3 Anti–lung cancer mechanism of TCM-combination therapy.

Abbreviations: Cur, curcumin; Rsv, resveratrol; Tmp, tetramethylpyrazine; Cts, cryptotanshinone; Qct, quercetin; Bbr, berberine; Dhb, dihydroberberine; GA, gambogic acid.

Figure 4 Anti–breast cancer mechanism of TCM-combination therapy.

Abbreviations: Cur, curcumin; Rsv, resveratrol; Bbr, berberine; Hcpt, hydroxycamptothecin; Qct, quercetin; GNA, gambogenic acid; BA, baicalein.

Figure 5 Passive (A) and active (B) targeting of tumors.

Abbreviation: EPR, enhanced permeability and retention.

Table 3 Polymeric nanoparticles (NPs) for codelivery of antitumor agents

Codelivery ingredients	Delivery-system materials	Method	Advantages	Reference
Epigallocatechin gallate (EGCG) + paclitaxel (Ptx)	Polylactic-co-glycolic acid (PLGA)–casein polymer– protein hybrid NPs	Emulsion precipitation	The core–shell nanoconstruct sequentially released EGCG followed by Ptx, which was sustained for 7 and 12 days, respectively. Compared with the bare drugs, dual-loaded NPs significantly increased plasma concentration, residence time, and circulatory half-life of nanoencapsulated Ptx and EGCG.	^Citation181
Camptothecin (CA) + ABT737	PEGylated polymeric NPs	Nanoencapsulation	Dual-loaded NPs exerted synergistic cytotoxic effects against HCT116 cells, RKO cells, and HT29 cells at a range of NP concentrations.	^Citation200
Gambogic acid (GA) + docetaxel (Dtx)	PLGA NPs	Nanoprecipitation	GA and Dtx were released synchronously in blood from the NPs in vivo. Compared with the saline control group, free Dtx solution and free Dtx-GA solution, the cocarrier NP-preparation group had the strongest inhibitory effect on the MCF7/ADR human breast-tumor xenograft.	^Citation201
Quercetin (Qct) + tamoxifen (Tmx)	PLGA NPs	Emulsion–diffusion solvent evaporation	NPs coencapsulated with Tmx and Qct had higher cellular uptake, cytotoxicity, and tumor suppression in female rats compared to free Tmx citrate, free Qct, and their combination.	^Citation202
Piperlongumine (PL) + Ptx	PLGA and -α-tocopheryl D PEG succinate NPs	Organic solvent evaporation	Compared with free Ptx, the double-loaded NPs had a sustained drug-release rate, showing increased cytotoxicity and cellular uptake in vitro. Ptx/PL-PT NPs suppressed tumor growth more efficiently with less toxicity than Ptx solution.	^Citation203
Qct + etoposide (Etp)	PLGA NPs	Single-emulsification (oil in water) solvent evaporation	With sustained release shown by NP pharmacokinetic parameters, bioavailability increased gradually. Cytotoxicity assays showed that the IC50 values of Etp-loaded NPs and Etp + Qct double-loaded NPs were nine- and elevenfold lower than free Etp.	^Citation199
Piperine + rapamycin	PLGA NPs	Nanoprecipitation	Dual-loaded NPs exhibited sustained release, with potential for long-term therapeutic action with less dosing frequency, and would result in a reduction of dosing and improved bioavailability compared to single-drug administration.	^Citation204
Vincristine (VI) + verapamil (VE)	PLGA NPs	Oil-in-water emulsion- solvent evaporation	The toxicity of coencapsulated NPs was lower than that of the free VI–VE combination. Compared with normal saline, free VI, free VI–VE combination, and single-drug NP combination, the coencapsulated NP group had the best tumor growth–inhibition effect in the MCF7/ADR human breast-tumor xenograft.	^Citation205

Abbreviation: PEG, polyethylene glycol.

Figure 6 Schematic illustrations of several nanosystems for drugs.

AnandPSundaramCJhuraniSKunnumakkaraABAggarwalBBCurcumin and cancer: an “old-age” disease with an “age-old” solutionCancer Lett2008267113316418462866

 PubMed Web of Science ®Google Scholar

DuvoixABlasiusRDelhalleSChemopreventive and therapeutic effects of curcuminCancer Lett2005223218119015896452

 PubMed Web of Science ®Google Scholar

ZhangTDChenGQWangZGWangZYChenSJChenZArsenic trioxide, a therapeutic agent for APLOncogene200120497146715311704843

 PubMed Web of Science ®Google Scholar

DograSBandiSViswanathanPGuptaSArsenic trioxide amplifies cisplatin toxicity in human tubular cells transformed by HPV-16 E6/E7 for further therapeutic directions in renal cell carcinomaCancer Lett20153562 Pt B95396125444910

 PubMedGoogle Scholar

WangXJiangFMuJArsenic trioxide attenuates the invasion potential of human liver cancer cells through the demethylation-activated microRNA-491Toxicol Lett20142272758324680928

 PubMedGoogle Scholar

JiangXChenCZhaoWZhangZSodium arsenite and arsenic tri-oxide differently affect the oxidative stress, genotoxicity and apoptosis in A549 cells: an implication for the paradoxical mechanismEnviron Toxicol Pharmacol201336389190224004876

 PubMedGoogle Scholar

WalkerAMStevensJJNdebeleKTchounwouPBEvaluation of arsenic trioxide potential for lung cancer treatment: assessment of apoptotic mechanisms and oxidative damageJ Cancer Sci Ther2016080119

 Google Scholar

AlkhalafMJaffalSPotent antiproliferative effects of resveratrol on human osteosarcoma SJSA1 cells: novel cellular mechanisms involving the ERKs/p53 cascadeFree Radic Biol Med200641231832516814113

 PubMedGoogle Scholar

PatelKRBrownVAJonesDJClinical pharmacology of resveratrol and its metabolites in colorectal cancer patientsCancer Res201070197392739920841478

 PubMed Web of Science ®Google Scholar

RaufAImranMButtMSNadeemMPetersDGMubarakMSResveratrol as an anti-cancer agent: a reviewCrit Rev Food Sci Nutr20185891428144728001084

 PubMed Web of Science ®Google Scholar

CaiHScottEKholghiACancer chemoprevention: evidence of a nonlinear dose response for the protective effects of resveratrol in humans and miceSci Transl Med20157298298ra117

 PubMedGoogle Scholar

OiNYuanJMalakhovaMResveratrol induces apoptosis by directly targeting Ras-GTPase-activating protein SH3 domain-binding protein 1Oncogene201534202660267124998844

 PubMedGoogle Scholar

ZouMWangJGaoJHanHFangYPhosphoproteomic analysis of the antitumor effects of ginsenoside Rg3 in human breast cancer cellsOncol Lett20181532889289829435015

 PubMedGoogle Scholar

YangXZouJCaiHGinsenoside Rg3 inhibits colorectal tumor growth via down-regulation of C/EBPβ/NF-κB signalingBiomed Pharmacother2017961240124529169725

 PubMedGoogle Scholar

LiuTZhaoLHouHDingLChenWLiXGinsenoside 20(S)-Rg3 suppresses ovarian cancer migration via hypoxia-inducible factor 1 alpha and nuclear factor-kappa B signalsTumour Biol2017395101042831769222

 Google Scholar

SuMQZhouYRRaoXBaicalein induces the apoptosis of HCT116 human colon cancer cells via the upregulation of DEPP/ Gadd45a and activation of MAPKsInt J Oncol201853275076029749481

 PubMed Web of Science ®Google Scholar

SongLChenXWangPGaoSQuCLiuLEffects of baicalein on pancreatic cancer stem cells via modulation of sonic hedgehog pathwayActa Biochim Biophys Sin201850658659629697746

 PubMedGoogle Scholar

ChaoJISuWCLiuH-FBaicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AktMol Cancer Ther20076113039304818025287

 PubMed Web of Science ®Google Scholar

ZhouQWangSZhangHThe combination of baicalin and baicalein enhances apoptosis via the ERK/p38 MAPK pathway in human breast cancer cellsActa Pharmacol Sin200930121648165819960010

 PubMed Web of Science ®Google Scholar

YanXIRuiXZhangKAIBaicalein inhibits the invasion of gastric cancer cells by suppressing the activity of the p38 signaling pathwayOncol Rep201533273774325502212

 PubMed Web of Science ®Google Scholar

WangYFLiTTangZHBaicalein triggers autophagy and inhibits the protein kinase B/Mammalian target of rapamycin pathway in hepatocellular carcinoma HepG2 cellsPhytother Res201529567467925641124

 PubMed Web of Science ®Google Scholar

WuJYTsaiKWLiYZAnti-Bladder-Tumor effect of baicalein from Scutellaria baicalensis Georgi and its application in vivoEvid Based Complement Alternat Med2013201357975123573134

 PubMed Web of Science ®Google Scholar

GuoZHuXXingZBaicalein inhibits prostate cancer cell growth and metastasis via the caveolin-1/AKT/mTOR pathwayMol Cell Biochem20154061–211111925957503

 PubMedGoogle Scholar

PengYGuoCYangYBaicalein induces apoptosis of human cervical cancer HeLa cells in vitroMol Med Rep20151132129213425373554

 PubMed Web of Science ®Google Scholar

ChandrashekarNSelvamaniASubramanianRPandiAThiruvengadamDBaicalein inhibits pulmonary carcinogenesis-associated inflammation and interferes with COX-2, MMP-2 and MMP-9 expressions in-vivoToxicol Appl Pharmacol20122611102122369883

 PubMed Web of Science ®Google Scholar

YuJGuoQLYouQDGambogic acid-induced G2/M phase cell-cycle arrest via disturbing CDK7-mediated phosphorylation of CDC2/p34 in human gastric carcinoma BGC-823 cellsCarcinogenesis200728363263817012222

 PubMed Web of Science ®Google Scholar

WangXDengRLuYGambogic acid as a non-competitive inhibitor of ATP-binding cassette transporter B1 reverses the multidrug resistance of human epithelial cancers by promoting ATP-binding cassette transporter B1 protein degradationBasic Clin Pharmacol Toxicol20131121253322759348

 PubMed Web of Science ®Google Scholar

WuZQGuoQLYouQDZhaoLGuH-YGambogic acid inhibits proliferation of human lung carcinoma SPC-A1 cells in vivo and in vitro and represses telomerase activity and telomerase reverse transcriptase mRNA expression in the cellsBiol Pharm Bull200427111769177415516720

 PubMed Web of Science ®Google Scholar

WangCZhangHChenYShiFChenBGambogic acid-loaded magnetic Fe(3)O(4) nanoparticles inhibit Panc-1 pancreatic cancer cell proliferation and migration by inactivating transcription factor ETS1Int J Nanomedicine2012778178722393285

 PubMed Web of Science ®Google Scholar

GuoQLYouQDWuZQYuanSTZhaoLGeneral gambogic acids inhibited growth of human hepatoma SMMC-7721 cells in vitro and in nude miceActa Pharmacol Sin200425676977415169630

 PubMed Web of Science ®Google Scholar

ZhuXZhangHLinYMechanisms of gambogic acid-induced apoptosis in non-small cell lung cancer cells in relation to transferrin receptorsJ Chemother200921666667220071291

 PubMed Web of Science ®Google Scholar

NieFZhangXQiQReactive oxygen species accumulation contributes to gambogic acid-induced apoptosis in human hepatoma SMMC-7721 cellsToxicology20092601–3606719464570

 PubMed Web of Science ®Google Scholar

YanFWangMChenHGambogenic acid mediated apoptosis through the mitochondrial oxidative stress and inactivation of Akt signaling pathway in human nasopharyngeal carcinoma CNE-1 cellsEur J Pharmacol20116521–3233221118682

 PubMed Web of Science ®Google Scholar

ChenHBZhouLZMeiLGambogenic acid-induced time- and dose-dependent growth inhibition and apoptosis involving Akt pathway inactivation in U251 glioblastoma cellsJ Nat Med2012661626921879332

 PubMedGoogle Scholar

WangKTangYSunMThe mechanism of neogambogic acid-induced apoptosis in human MCF-7 cellsActa Biochim Biophys Sin201143969870221785112

 PubMedGoogle Scholar

MeiWDongCHuiCGambogenic acid kills lung cancer cells through aberrant autophagyPLoS One201491e8360424427275

 PubMedGoogle Scholar

LiQChengHZhuGGambogenic acid inhibits proliferation of A549 cells through apoptosis-inducing and cell cycle arrestingBiol Pharm Bull201033341542020190402

 PubMed Web of Science ®Google Scholar

ChengHSuJJPengJYGambogenic acid inhibits proliferation of A549 cells through apoptosis inducing through up-regulation of the p38 MAPK cascadeJ Asian Nat Prod Res20111311993100222007630

 PubMed Web of Science ®Google Scholar

ZhangXXuQSaikiIQuercetin inhibits the invasion and mobility of murine melanoma B16-BL6 cells through inducing apoptosis via decreasing Bcl-2 expressionClin Exp Metastasis200018541542111467774

 PubMedGoogle Scholar

CalgarottoAKMasoVJuniorGCAntitumor activities of quercetin and green tea in xenografts of human leukemia HL60 cellsSci Rep201881345929472583

 PubMed Web of Science ®Google Scholar

TsaiPHChengCHLinC-YDietary flavonoids luteolin and quercetin suppressed cancer stem cell properties and metastatic potential of isolated prostate cancer cellsAnticancer Res201636126367638027919958

 PubMed Web of Science ®Google Scholar

JiaLHuangSYinXZanYGuoYHanLQuercetin suppresses the mobility of breast cancer by suppressing glycolysis through Akt-mTOR pathway mediated autophagy inductionLife Sci201820812313030025823

 PubMed Web of Science ®Google Scholar

Anand DavidAVArulmoliRParasuramanSOverviews of biological importance of quercetin: a bioactive flavonoidPharmacogn Rev20161020848928082789

 PubMedGoogle Scholar

LugliEFerraresiRRoatEQuercetin inhibits lymphocyte activation and proliferation without inducing apoptosis in peripheral mononuclear cellsLeuk Res200933114015018774171

 PubMedGoogle Scholar

ZhangHLiHLiuZTriptolide inhibits the proliferation and migration of medulloblastoma DAOY cells by upregulation of microRNA-138J Cell Biochem2018119129866987730156009

 PubMed Web of Science ®Google Scholar

MaoXTongJWangYZhuZYinYWangYTriptolide exhibits antitumor effects by reversing hypermethylation of WIF1 in lung cancer cellsMol Med Rep20181833041304930015908

 PubMed Web of Science ®Google Scholar

ZhouZLYangYXDingJLiYCMiaoZ-HTriptolide: structural modifications, structure-activity relationships, bioactivities, clinical development and mechanismsNat Prod Rep201229445747522270059

 PubMed Web of Science ®Google Scholar

LiSGShiQWYuanLYC-Myc-dependent repression of two oncogenic miRNA clusters contributes to triptolide-induced cell death in hepatocellular carcinoma cellsJ Exp Clin Cancer Res2018375129523159

 PubMed Web of Science ®Google Scholar

WangYLiuTLiHEnhancement of triptolide-loaded micelles on tumorigenicity inhibition of human ovarian cancerJ Biomater Sci Polym Ed201627754555626786618

 PubMed Web of Science ®Google Scholar

HuGGongXWangLTriptolide promotes the clearance of α-synuclein by enhancing autophagy in neuronal cellsMol Neurobiol20175432361237226957304

 PubMedGoogle Scholar

KimSHKangJGKimCSSynergistic cytotoxicity of BIIB021 with triptolide through suppression of PI3K/AKT/mTOR and NF-κB signal pathways in thyroid carcinoma cellsBiomed Pharmacother201683223227470546

 PubMedGoogle Scholar

LiWYangYHuZLingSFangMNeuroprotective effects of DAHP and triptolide in focal cerebral ischemia via apoptosis inhibition and PI3K/Akt/mTOR pathway activationFront Neuroanat201594825954164

 PubMed Web of Science ®Google Scholar

YaoZWanYLiBBerberine induces mitochondrialmediated apoptosis and protective autophagy in human malignant pleural mesothelioma NCIH2452 cellsOncol Rep20184063603361030272347

 PubMedGoogle Scholar

FukudaKHibiyaYMutohMKoshijiMAkaoSFujiwaraHInhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cellsJ Ethnopharmacol199966222723310433483

 PubMed Web of Science ®Google Scholar

WangZWangY-SChangZ-MBerberine-loaded Janus nanocarriers for magnetic field-enhanced therapy against hepatocellular carcinomaChem Biol Drug Des201789346446927618577

 PubMed Web of Science ®Google Scholar

KuoHPChuangTCYehMHGrowth suppression of HER2-overexpressing breast cancer cells by berberine via modulation of the HER2/PI3K/AKT signaling pathwayJ Agric Food Chem201159158216822421699261

 PubMed Web of Science ®Google Scholar

KimSHanJLeeSKBerberine suppresses the TPA-induced MMP-1 and MMP-9 expressions through the inhibition of PKC-α in breast cancer cellsJ Surg Res20121761e21e2922381172

 PubMedGoogle Scholar

LinCCYangJSChenJTBerberine induces apoptosis in human HSC-3 oral cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathwayAnticancer Res2007275A3371337817970083

 PubMedGoogle Scholar

MantenaSKSharmaSDKatiyarSKBerberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki-Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PARPCarcinogenesis200627102018202716621886

 PubMedGoogle Scholar

ShinDSKimHNShinKDCryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cellsCancer Res200969119320219118003

 PubMed Web of Science ®Google Scholar

ChenWLuoYLiuLCryptotanshinone inhibits cancer cell proliferation by suppressing mammalian target of rapamycin-mediated cyclin D1 expression and RB phosphorylationCancer Prev Res20103810151025

 PubMed Web of Science ®Google Scholar

ChenLWangHJXieWYaoYZhangYSWangHCryptotanshinone inhibits lung tumorigenesis and induces apoptosis in cancer cells in vitro and in vivoMol Med Rep2014962447245224682389

 PubMed Web of Science ®Google Scholar

XiaoWZhuMXZhuMXPanXJYangZHZhouS-YInhibition of cyclooxygenase-2 by tetramethylpyrazine and its effects on A549 cell invasion and metastasisInt J Oncol20124062029203722344367

 PubMedGoogle Scholar

WangYFuQZhaoWTetramethylpyrazine inhibits osteosarcoma cell proliferation via downregulation of NF-κB in vitro and in vivoMol Med Rep20138498498823912183

 PubMedGoogle Scholar

WangSJGaoYChenHDihydroartemisinin inactivates NF-kappaB and potentiates the anti-tumor effect of gemcitabine on pancreatic cancer both in vitro and in vivoCancer Lett201029319910820137856

 PubMed Web of Science ®Google Scholar

JiYZhangYCPeiLBShiLLYanJLMaXHAnti-tumor effects of dihydroartemisinin on human osteosarcomaMol Cell Biochem20113511–29910821234653

 PubMedGoogle Scholar

GaoXLuoZXiangTWangKLiJWangPDihydroartemisinin induces endoplasmic reticulum stress-mediated apoptosis in HepG2 human hepatoma cellsTumori201197677178022322845

 PubMedGoogle Scholar

LaiHSinghNPSelective cancer cell cytotoxicity from exposure to dihydroartemisinin and holotransferrinCancer Lett199591141467750093

 PubMed Web of Science ®Google Scholar

LaiHSasakiTSinghNPMessayAEffects of artemisinin-tagged holotransferrin on cancer cellsLife Sci200576111267127915642597

 PubMedGoogle Scholar

ChenHGuSDaiHLiXZhangZDihydroartemisinin sensitizes human lung adenocarcinoma A549 cells to arsenic trioxide via apoptosisBiol Trace Elem Res2017179220321228261759

 PubMedGoogle Scholar

OhMChoiYHChoiSAnti-proliferating effects of ginsenoside Rh2 on MCF-7 human breast cancer cellsInt J Oncol199914586987510200336

 PubMedGoogle Scholar

NakataHKikuchiYTodeTInhibitory effects of ginsenoside Rh2 on tumor growth in nude mice bearing human ovarian cancer cellsJpn J Cancer Res19988977337409738980

 PubMedGoogle Scholar

XieXEberdingAMaderaCRh2 synergistically enhances paclitaxel or mitoxantrone in prostate cancer modelsJ Urol200617551926193116600800

 PubMed Web of Science ®Google Scholar

XiaTWangYNZhouCXGinsenoside Rh2 and Rg3 inhibit cell proliferation and induce apoptosis by increasing mitochondrial reactive oxygen species in human leukemia Jurkat cellsMol Med Rep20171563591359828440403

 PubMedGoogle Scholar

YangJYuanDXingTGinsenoside Rh2 inhibiting HCT116 colon cancer cell proliferation through blocking PDZ-binding kinase/T-LAK cell-originated protein kinaseJ Ginseng Res201640440040827746693

 PubMed Web of Science ®Google Scholar

YangZZhaoTLiuHZhangLGinsenoside Rh2 inhibits hepatocellular carcinoma through β-catenin and autophagySci Rep2016611938326783250

 PubMedGoogle Scholar

HuangJPengKWangLGinsenoside Rh2 inhibits proliferation and induces apoptosis in human leukemia cells via TNF-α signaling pathwayActa Biochim Biophys Sin201648875075527177748

 PubMedGoogle Scholar

LiSGaoYMaWEGFR signaling-dependent inhibition of glioblastoma growth by ginsenoside Rh2Tumor Biol201435655935598

 PubMedGoogle Scholar

HanSJeongAJYangHGinsenoside 20(S)-Rh2 exerts anticancer activity through targeting IL-6-induced JAK2/STAT3 pathway in human colorectal cancer cellsJ Ethnopharmacol2016194839027566200

 PubMedGoogle Scholar

GuanNHuoXZhangZZhangSLuoJGuoWGinsenoside Rh2 inhibits metastasis of glioblastoma multiforme through Akt-regulated MMP13Tumor Biol201536967896795

 PubMedGoogle Scholar

AbedinpourPBaronVTChrastinaAPlumbagin improves the efficacy of androgen deprivation therapy in prostate cancer: a pre-clinical studyProstate201777161550156228971491

 PubMedGoogle Scholar

KawiakADomachowskaAPlumbagin suppresses the invasion of HER2-overexpressing breast cancer cells through inhibition of IKKα-Mediated NF-κB activationPLoS One20161110e016406427727280

 PubMedGoogle Scholar

OhTIYunJMParkEJPlumbagin suppresses α-MSH-Induced melanogenesis in B16F10 mouse melanoma cells by inhibiting tyrosinase activityInt J Mol Sci2017182320

 PubMedGoogle Scholar

LiuYCaiYHeCChenMLiHAnticancer properties and pharmaceutical applications of plumbagin: a reviewAm J Chin Med201745342344128359198

 PubMedGoogle Scholar

ZhangWShiHChenCCurcumin enhances cisplatin sensitivity of human NSCLC cell lines through influencing Cu-Sp1-CTR1 regulatory loopPhytomedicine201848516130195880

 PubMedGoogle Scholar

ZhanYChenYLiuRZhangHZhangYPotentiation of paclitaxel activity by curcumin in human breast cancer cell by modulating apoptosis and inhibiting EGFR signalingArch Pharm Res20143781086109524318305

 PubMed Web of Science ®Google Scholar

MohapatraPSatapathySRSiddharthSDasDNayakAKunduCNResveratrol and curcumin synergistically induces apoptosis in cigarette smoke condensate transformed breast epithelial cells through a p21(Waf1/Cip1) mediated inhibition of Hh-Gli signalingInt J Biochem Cell Biol201566758426212257

 PubMed Web of Science ®Google Scholar

MajumdarAPBanerjeeSNautiyalJCurcumin synergizes with resveratrol to inhibit colon cancerNutr Cancer200961454455319838927

 PubMed Web of Science ®Google Scholar

MasuelliLMarzocchellaLFocaccettiCResveratrol and diallyl disulfide enhance curcumin-induced sarcoma cell apoptosisFront Biosci2012171498508

 Google Scholar

SánchezYSimónGPCalviñoEde BlasEAllerPCurcumin stimulates reactive oxygen species production and potentiates apoptosis induction by the antitumor drugs arsenic trioxide and lonidamine in human myeloid leukemia cell linesJ Pharmacol Exp Ther2010335111412320605902

 PubMedGoogle Scholar

FehlDJAhmedMCurcumin promotes the oncoltyic capacity of vesicular stomatitis virus for the treatment of prostate cancersVirus Res2017228142327865863

 PubMedGoogle Scholar

ZhangJYLinMTZhouMJCombinational treatment of cur-cumin and quercetin against gastric cancer MGC-803 cells in vitroMolecules2015206115241153426111180

 PubMed Web of Science ®Google Scholar

LiYFengLLiYJiangWShanNWangXArtesunate possesses anti-leukemia properties that can be enhanced by arsenic trioxideLeuk Lymphoma20145561366137223906016

 PubMed Web of Science ®Google Scholar

TomuleasaCSoritauOFischer-FodorEArsenic trioxide plus cisplatin/interferon α-2b/doxorubicin/capecitabine combination chemotherapy for unresectable hepatocellular carcinomaHematol Oncol Stem Cell Ther201142606621727766

 PubMedGoogle Scholar

WangWQinSKChenBAChenHYExperimental study on antitumor effect of arsenic trioxide in combination with cisplatin or doxorubicin on hepatocellular carcinomaWorld J Gastroenterol20017570270511819858

 PubMedGoogle Scholar

ZhaoYYYuLLiuBLHeXJZhangB-YDownregulation of P-gp, Ras and p-ERK1/2 contributes to the arsenic trioxide-induced reduction in drug resistance towards doxorubicin in gastric cancer cell linesMol Med Rep20151257335734326459009

 PubMed Web of Science ®Google Scholar

YuQChenBZhangXQianWYeBZhouYArsenic trioxide-enhanced, matrine-induced apoptosis in multiple myeloma cell linesPlanta Med2013790977578123700110

 PubMedGoogle Scholar

HuSLiXXuRThe synergistic effect of resveratrol in combination with cisplatin on apoptosis via modulating autophagy in A549 cellsActa Biochim Biophys Sin201648652853527084520

 PubMedGoogle Scholar

RaiGMishraSSumanSShuklaYResveratrol improves the anticancer effects of doxorubicin in vitro and in vivo models: a mechanistic insightPhytomedicine201623323324226969377

 PubMedGoogle Scholar

JiangQYangMQuZZhouJZhangQResveratrol enhances anticancer effects of paclitaxel in HepG2 human liver cancer cellsBMC Complement Altern Med201717147728978315

 PubMedGoogle Scholar

KongFZhangRZhaoXZhengGWangZWangPResveratrol raises in vitro anticancer effects of paclitaxel in NSCLC cell line A549 through COX-2 expressionKorean J Physiol Pharmacol201721546547428883751

 PubMedGoogle Scholar

YuanYXueXGuoRBSunXLHuGResveratrol enhances the antitumor effects of temozolomide in glioblastoma via ROS-dependent AMPK-TSC-mTOR signaling pathwayCNS Neurosci Ther201218753654622530672

 PubMed Web of Science ®Google Scholar

Tomas-HernándezSBlancoJRojasCResveratrol potently counteracts quercetin starvation-induced autophagy and sensitizes HepG2 cancer cells to apoptosisMol Nutr Food Res20186251700610

 Google Scholar

ZhaoXYYangSChenYRLiPCDouMMZhangJResveratrol and arsenic trioxide act synergistically to kill tumor cells in vitro and in vivoPLoS One201496e9892524901647

 PubMedGoogle Scholar

CheJBLiuZHMaHBInfluence of As2O3 combined with ginsenosides Rg3 on inhibition of lung cancer NCI-H1299 cells and on subsistence of nude mice bearing hepatomaAsian Pac J Trop Med201471077277525129458

 PubMedGoogle Scholar

YuanZJiangHZhuXLiuXLiJGinsenoside Rg3 promotes cytotoxicity of paclitaxel through inhibiting NF-κB signaling and regulating Bax/Bcl-2 expression on triple-negative breast cancerBiomed Pharmacother20178922723228231544

 PubMed Web of Science ®Google Scholar

ChangLHuoBLvYWangYLiuWGinsenoside Rg3 enhances the inhibitory effects of chemotherapy on esophageal squamous cell carcinoma in miceMol Clin Oncol2014261043104625279195

 PubMedGoogle Scholar

KimSMLeeSYYukDYInhibition of NF-kappaB by ginsenoside Rg3 enhances the susceptibility of colon cancer cells to docetaxelArch Pharm Res200932575576519471891

 PubMed Web of Science ®Google Scholar

PanQXueMXiaoS-SWanY-JXuD-BA combination therapy with baicalein and taxol promotes mitochondria-mediated cell apoptosis: involving in Akt/β-Catenin signaling pathwayDNA Cell Biol2016351164665627414207

 PubMedGoogle Scholar

TangQJiFSunWCombination of baicalein and 10-hydroxy camptothecin exerts remarkable synergetic anti-cancer effectsPhytomedicine201623141778178627912880

 PubMedGoogle Scholar

WangLHLiYYangSNGambogic acid synergistically potentiates cisplatin-induced apoptosis in non-small-cell lung cancer through suppressing NF-κB and MAPK/HO-1 signallingBr J Cancer2014110234135224300974

 PubMed Web of Science ®Google Scholar

XiaGWangHSongZMengQHuangXHuangXGambogic acid sensitizes gemcitabine efficacy in pancreatic cancer by reducing the expression of ribonucleotide reductase subunit-M2 (RRM2)J Exp Clin Cancer Res201736110728797284

 PubMedGoogle Scholar

JiangXLZhangYLuoCLWuXHTargeting renal cell carcinoma with gambogic acid in combination with sunitinib in vitro and in vivoAsian Pac J Cancer Prev201213126463646823464475

 PubMedGoogle Scholar

HeYDingJLinYGambogenic acid alters chemosensitivity of breast cancer cells to adriamycinBMC Complement Altern Med201515118126066793

 PubMedGoogle Scholar

ChenRZhangHLiuPWuXChenBGambogenic acid synergistically potentiates bortezomib-induced apoptosis in multiple myelomaJ Cancer20178583985128382147

 PubMedGoogle Scholar

MaZSHuynhTHNgCPDoPTNguyenTHHuynhHReduction of CWR22 prostate tumor xenograft growth by combined tamoxifen-quercetin treatment is associated with inhibition of angiogenesis and cellular proliferationInt J Oncol20042451297130415067354

 PubMed Web of Science ®Google Scholar

SunSGongFLiuPMiaoQMetformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of VEGF/ PI3K/Akt signaling pathwayGene2018664505729678660

 PubMed Web of Science ®Google Scholar

ChanSTChuangCHLinYCLiaoJWLiiCKYehS-LQuercetin enhances the antitumor effect of trichostatin A and suppresses muscle wasting in tumor-bearing miceFood Funct20189287187929292417

 PubMedGoogle Scholar

TangQJiFWangJGuoLLiYBaoYQuercetin exerts synergetic anti-cancer activity with 10-hydroxy camptothecinEur J Pharm Sci201710922323228822757

 PubMed Web of Science ®Google Scholar

LeiCSHouYCPaiMHLinMTYehS-LEffects of quercetin combined with anticancer drugs on metastasis-associated factors of gastric cancer cells: in vitro and in vivo studiesJ Nutr Biochem20185110511329125991

 PubMed Web of Science ®Google Scholar

AlsaiedOASangwanVBanerjeeSSorafenib and triptolide as combination therapy for hepatocellular carcinomaSurgery2014156227027924953273

 PubMedGoogle Scholar

LiCJChuCYHuangLHSynergistic anticancer activity of triptolide combined with cisplatin enhances apoptosis in gastric cancer in vitro and in vivoCancer Lett2012319220321322306340

 PubMedGoogle Scholar

MatsuiYWatanabeJIkegawaMKamotoTOgawaONishiyamaHCancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3beta with p53Oncogene200827334603461418391982

 PubMedGoogle Scholar

LiuYXiaoEYuanLLiGTriptolide Synergistically Enhances Antitumor Activity of Oxaliplatin in Colon Carcinoma In Vitro and In VivoDNA Cell Biol201433741842524720675

 PubMedGoogle Scholar

TangXYZhuYQTaoWHWeiBLinXLSynergistic effect of triptolide combined with 5-fluorouracil on colon carcinomaPostgrad Med J20078397933834317488865

 PubMedGoogle Scholar

QiaoZHeMHeMUSynergistic antitumor activity of gemcitabine combined with triptolide in pancreatic cancer cellsOncol Lett20161153527353327123146

 PubMed Web of Science ®Google Scholar

PanYZhangFZhaoYBerberine enhances chemosensitivity and induces apoptosis through Dose-orchestrated AMPK signaling in breast cancerJ Cancer2017891679168928775788

 PubMed Web of Science ®Google Scholar

ZhuTLiLLXiaoGFBerberine increases doxorubicin sensitivity by suppressing STAT3 in lung cancerAm J Chin Med20154371487150226503561

 PubMedGoogle Scholar

DuJSunYLuYYBerberine and evodiamine act synergistically against human breast cancer MCF-7 cells by inducing cell cycle arrest and apoptosisAnticancer Res201737116141615129061795

 PubMedGoogle Scholar

RenKZhangWWuGSynergistic anti-cancer effects of galangin and berberine through apoptosis induction and proliferation inhibition in oesophageal carcinoma cellsBiomed Pharmacother2016841748175927876206

 PubMed Web of Science ®Google Scholar

WenCWuLFuLZhangXZhouHBerberine enhances the anti-tumor activity of tamoxifen in drugsensitive MCF7 and drugresistant MCF7/TAM cellsMol Med Rep20161432250225627432642

 PubMedGoogle Scholar

HuangYWangKGuCBerberine, a natural plant alkaloid, synergistically sensitizes human liver cancer cells to sorafenibOncol Rep20184031525153230015938

 PubMed Web of Science ®Google Scholar

WangCJWangCHanJEffect of combined treatment with recombinant interleukin-2 and allicin on pancreatic cancerMol Biol Rep201340126579658524135803

 PubMedGoogle Scholar

ZouXLiangJSunJAllicin sensitizes hepatocellular cancer cells to anti-tumor activity of 5-fluorouracil through ROS-mediated mitochondrial pathwayJ Pharmacol Sci2016131423324027177453

 PubMed Web of Science ®Google Scholar

DaiBMaYWangWDihydroberberine exhibits synergistic effects with sunitinib on NSCLC NCI-H460 cells by repressing MAP kinase pathways and inflammatory mediatorsJ Cell Mol Med201721102573258528444871

 PubMedGoogle Scholar

LiuYBiTWangZOxymatrine synergistically enhances antitumor activity of oxaliplatin in colon carcinoma through PI3K/ Akt/mTOR pathwayApoptosis201621121398140727671687

 PubMedGoogle Scholar

SongMQZhuJSChenJLSynergistic effect of oxymatrine and angiogenesis inhibitor NM-3 on modulating apoptosis in human gastric cancer cellsWorld J Gastroenterol200713121788179317465467

 PubMedGoogle Scholar

ByunJMJeongDHLeeDSTetraarsenic oxide and cisplatin induce apoptotic synergism in cervical cancerOncol Rep20132941540154623338680

 PubMed Web of Science ®Google Scholar

XiaCBaiXHouXCryptotanshinone reverses cisplatin resistance of human lung carcinoma A549 cells through down-regulating Nrf2 pathwayCell Physiol Biochem201537281682426356271

 PubMedGoogle Scholar

TangJHZhangHMZhangZHZhangX-LEffect of tetramethylpyrazine combined with cisplatin on VEGF, KLF4 and ADAMTS1 in Lewis lung cancer miceAsian Pac J Trop Med201710881381828942831

 PubMedGoogle Scholar

Castillo-PichardoLDharmawardhaneSFGrape polyphenols inhibit Akt/mammalian target of rapamycin signaling and potentiate the effects of gefitinib in breast cancerNutr Cancer20126471058106923061908

 PubMed Web of Science ®Google Scholar

StearnsMEAmatangeloMDVarmaDSellCGoodyearSMCombination therapy with epigallocatechin-3-gallate and doxorubicin in human prostate tumor modeling studies: inhibition of metastatic tumor growth in severe combined immunodeficiency miceAm J Pathol201017763169317920971741

 PubMed Web of Science ®Google Scholar

LiangGTangALinXGreen tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancerInt J Oncol201037111112320514403

 PubMed Web of Science ®Google Scholar

NarayananSPavithranMViswanathASequentially releasing dual-drug-loaded PLGA-casein core/shell nanomedicine: design, synthesis, biocompatibility and pharmacokineticsActa Biomater20141052112212424389318

 PubMed Web of Science ®Google Scholar

SchmidDJarvisGEFayFNanoencapsulation of ABT-737 and camptothecin enhances their clinical potential through synergistic antitumor effects and reduction of systemic toxicityCell Death Dis2014510e145425299779

 PubMedGoogle Scholar

XuYWangCDingYNanoparticles with optimal ratiometric co-delivery of docetaxel with gambogic acid for treatment of multidrug-resistant breast cancerJ Biomed Nanotechnol20161291774178129345888

 PubMed Web of Science ®Google Scholar

JainAKThankiKJainSCo-encapsulation of tamoxifen and quercetin in polymeric nanoparticles: implications on oral bioavailability, antitumor efficacy, and drug-induced toxicityMol Pharm20131093459347423927416

 PubMed Web of Science ®Google Scholar

LiuQZhaoDZhuXColoaded nanoparticles of paclitaxel and Piperlongumine for enhancing synergistic antitumor activities and reducing toxicityJ Pharm Sci2017106103066307528552690

 PubMedGoogle Scholar

FatmaSTalegaonkarSIqbalZNovel flavonoid-based biodegradable nanoparticles for effective oral delivery of etoposide by P-glycoprotein modulation: an in vitro, ex vivo and in vivo investigationsDrug Deliv201623250051124937381

 PubMed Web of Science ®Google Scholar

KatiyarSSMuntimaduguERafeeqiTADombAJKhanWCo-delivery of rapamycin- and piperine-loaded polymeric nanoparticles for breast cancer treatmentDrug Deliv2016232608261626036652

 PubMed Web of Science ®Google Scholar

ChenYZhengXLFangDLDual agent loaded PLGA nanoparticles enhanced antitumor activity in a multidrug-resistant breast tumor eenograft modelInt J Mol Sci20141522761277224552875

 PubMedGoogle Scholar