Metabolite Profiling in Anticancer Drug Development: A Systematic Review

Figures & data

Table 1 Metabolism Studies (Metabolite Profiling) of Conventional Synthetic Anticancer Drugs

Anticancer Drug	Type of Study	Biochemical Tool/Animal/Human (Route: Dose)	Type of Sample	Analytical Technique	Outcome			Ref.
					Metabolite	Metabolic Pathway	Efficacy/Toxicity of Metabolite
AM6−36 (3-amino-6-(3′-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione)	In vitro	HLM, human hepatocyte	–	HPLC-QTOF-MS, HPLC-QqQ-MS	1 Metabolite for HLM (4); 7 Metabolites for hepatocyte (4–10)	Reduction (4); Monoacetylation (5); Conversion of amino acid group to an alcohol (7); Reduction of the ketone to an alcohol +conversion of amino acid group to an alcohol (8); Reduction + acetylation (6); Monoacetylation + conversion of amino acid group to an alcohol (9); Glucuronidation (10)	Metabolites 5: lower retinoid X receptor (RXR) homodimers bind to DNA response elements (RXRE) induction activity than parent compound AM6-36 Metabolites 8: exhibited lower activity to inhibit NFƘB than AM6-36	[^Citation13]
	In vivo	Female Sprague−Dawley rats (PO: 40 mg/kg)	Serum, liver, mammary tissues		1 Metabolites for serum (5); 5 Metabolites for liver tissue (4, 5, and 7–9); No metabolite in mammary tissue
ARQ 501 (synthetic β-lapachone)	In vitro	Mouse, rat, dog, monkey, human whole blood	–	UPLC-QTOF-MS, HPLC-MS-ARC	4 Metabolites for mouse and rat (M1, M2, M3, M5); 5 Metabolites for dog (M1, M2, M3, M5, unidentified metabolite); 5 Metabolites for monkey (M1, M2, M3, M5, M6); 6 Metabolites for human (M1, M2, M3, M4, M5, M6); ARQ 501 disappeared after 60 min of incubation in human whole blood	Oxidation (M1); Adding 2 oxygen and 2 hydrogen atoms (M2); Adding 1 oxygen and 2 hydrogen atoms (M3); Loss of 1 carbon atom (M4 and M6); Loss of CO group (M5)	Not evaluated	[^Citation14]
ARQ 501 (synthetic β-lapachone)	In vivo	Mice (IP: 40 mg/kg), rats (IV: 40 mg/kg)	Plasma	LC-QTOF-MS, HPLC-QqQ-MS	3 Metabolites for all species	Glucosylation + sulfation; Glucuronidation; Sulfation	Not evaluated	[^Citation15]
	Clinical trial	Cancer patients (140 mg/m^2)			3 Metabolites
Cabazitaxel	Phase I clinical trial	Advanced solid tumor patients (IV: 25 mg/m^2 of [^14C]-cabazitaxel (50 muCi, 1.85 MBq of [^14C]-cabazitaxel))	Plasma, urine, feces	HPLC-RD-MS	6 Metabolites in plasma (Major: RPR123142); 10 Metabolites in urine (Major: M09b); 13 Metabolites in feces (Major: RPR104943, RPR104952, RPR111026, RPR111059)	7-O-demethylation + 10-O-demethylation + hydroxylation (RPR104952); 10-O-demethylation (RPR123142); 7-O-demethylation + 10-O-demethylation + di-hydroxylation (M09b); 7-O-demethylation + di-hydroxylation + 10-O-demethylation (RPR111026, RPR111059); 7-O-demethylation + di-hydroxylation + 10-O-demethylation + hydroxylation (RPR104943); Cleavage is minor pathway plasma and urine	Not evaluated	[^Citation16]
Capecitabine	In vivo	Male Wistar rats (PO: 80 mg/kg)	Bile, urine, liver, kidneys	HPLC-TIS-MS/MS, ^19F-NMR and ^1H-NMR	3 Metabolites for liver (5ʹ-deoxy-5-fluorocytidine, α-Fluoro-β-alanine, 2ʹ-(β-D-glucuronic acid)-5ʹ-deoxy-5-fluorocytidine); 2 Metabolites for bile (5ʹ-deoxy-5-fluorocytidine, 2ʹ-(β-D-glucuronic acid)–5ʹ-deoxy-5-fluorocytidine); 2 Metabolites for kidney (5ʹ-deoxy-5-fluorocytidine, α-Fluoro-β-alanine); 4 Metabolites for urine (5ʹ-deoxy-5-fluorouridine, 5.6-Dihydro-5-fluorouracil, α-Fluoro-β-alanine, 5ʹ-deoxy-5-fluorocytidine)	Glucuronidation (2ʹ-(β-D-glucuronic acid)-5ʹ-deoxy-5-fluorocytidine); Not identified (5ʹ-deoxy-5-fluorocytidine, α-fluoro-β-alanine, 5ʹ-deoxy-5-fluorouridine, 5.6-Dihydro-5-fluorouracil)	Not evaluated	[^Citation17]
Carbendazim (2-benzimidazolecarbamic acid methyl ester)	In vitro	RLM, HLM	–	HPLC-ESI-MS	1 Metabolite (5(6)- or 4(7)-hydroxyl carbendazim)	Oxidation	Not evaluated	[^Citation18]
	In vivo	Rats (PO: 1000 mg/kg)	Serum		1 Metabolite (2-aminobenzimidazole)	Hydrolysis
CI941 (losoxantrone)	In vitro	Rat hepatocyte, human hepatoblastoma (HepG2) cell lines	–	HPLC-UV, HPLC-QqQ-MS, ^1H-NMR	12 Metabolites (M2-M13) for rat hepatocyte; No metabolite in HepG2	Hydroxylation (M2, M3); Hydroxylation + oxidation (M8); Hydroxylation + oxidation + glutathione conjugation (M10); Hydroxylation+ glucuronidation (M4, M9); Hydroxylation + sulfation (M5-M7); Oxidation (M11-M13)	Not evaluated	[^Citation19]
Cisplatin	In vivo	Male Sprague-Dawley rats (IV: 3mg/kg)	Kidney tissue	HPLC-ESI-QTOF-MS	31 Metabolites (M1-M31)	Hydration (M1); Hydroxylation (M4); Dihydroxylation (M3); Methionine conjugation (M5); Di-methionine conjugation (M15, M29); Cysteine conjugation (M7, M8); Di-cysteine conjugation (M16, M31); Chlorination (M24, M26); Acetylcysteine conjugation (M9, M10); Di-acetylcysteine conjugation (M17); Glutathione conjugation (M11); Thioether conjugation (M13); Hydration+ hydroxylation (M2); Methionine conjugation + hydroxylation (M6); Methionine conjugation + chelation (M18, M20, M25); Methionine conjugation + chelation + hydroxylation (M19); Cysteine conjugation+ chelation (M21, M23, M27, M28, M30); Cysteine conjugation+ chelation + hydroxylation (M22); Glutathione conjugation +hydroxylation (M12); Thioether conjugation + hydroxylation (M14)	Not evaluated	[^Citation20]
CP-31398 (N’-[2-[2-(4-methoxyphenyl)ethenyl)-4-quinazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride)	In vivo	Male and Female CD rats (PO: 0, 240, 480, or 960 mg/m^2/day) and beagle dogs (0, 200, 400, or 800 mg/m^2/day)	Plasma	HPLC-QTOF-MS	4 Metabolites for rat (II: hydroxy CP-31398, III: O-demethyl CP-31398, IV: N-demethyl CP-31398, V: hydroxy O-demethyl CP-31398); 4 Metabolites for dog (II: hydroxy CP-31398, III: O-demethyl CP-31398, IV: N-demethyl CP-31398, VI: di-demethyl CP-31398)	Hydroxylation (hydroxy CP-31398); O-demethylation (O-demethyl CP-31398); N-demethylation (N-demethyl CP-31398); Hydroxylation + O-demethylation (hydroxy O-demethyl CP-31398); Di-demethylation (di-demethyl CP-31398)	Not evaluated	[^Citation21]
CPA (Cyproterone acetate)	In vivo	Female Wistar-Han rats (PO: 50 mg/kg [^3H] CPA (0.42 MBq/mg))	Bile	HPLC-MS, GC-MS, ^1H-NMR	2 Metabolites (M1: 3α-OH-CPA and M2)	Sulfation and/or Glucuronidation	3α-OH-CPA covalently bound to guanine which might be the major adduct formed of CPA	[^Citation22]
Crisnatol	In vitro	Human hepatoma (Hep G2) cells, HLM	–	GC-MS, ^1H-NMR	3 Metabolites for Hep G2 (M1 and M2: isomeric crisnatol dihydrodiol and M3: crisnatol 1,2-dihydrodiol); 2 Metabolites for HLM (M4: crisnatol 1,2-dihydrodiol and M5: 1-hydroxycrisnatol)	Di-hydroxylation + di-hydrogenation (M3, M4); Hydroxylation (M5)	Not evaluated	[^Citation23]
Cyclophosphamide	Clinical trial	Cancer patients (60 mg/kg)	Plasma, urine	GC-MS	1 Active metabolite for both samples (N, N-bis(2-chloroethyl) phosphorodiamidic acid)	Not identified	Not evaluated	[^Citation24]
DFS (Trans-2,6-difluoro-4ʹ-(N, N)-dimethylamino) stilbene: Stilbene analog)	In vitro	Pooled MLM, RLM, HLM	–	HPLC-ESI-MS/MS	10 Metabolites for MLM (M1-10); 7 Metabolites for RLM (M1, M3-6, M9-10); 6 Metabolites for HLM (M1-3, M5, M7, M10)	Demethylation (M1); Oxidation (M2-M4); Demethylation + Oxidation (M5); Oxidation + Defluorination (M6, M7); Bisoxidation (M8, M9); Isomerization (M10)	Not evaluated	[^Citation25]
5ʹ-dFUR (5ʹ-deoxy-5-fluorouridine)	In vivo	Cancer patients (IV: 4 g/m^2)	Plasma	GC-MS	3 Metabolites (N^3-Methylated-5ʹ-dFUR, 5-fluorouracil, and 5,6-dihydro-5-fluorouracil)	Methylation (N^3-Methylated-5ʹ-dFUR); Not identified (5-fluorouracil, and 5,6-dihydro-5-fluorouracil)	Not evaluated	[^Citation27]
5ʹ-dFUrd (5ʹ-deoxy-5-fluorouridine)	Clinical trial	Cancer patients (IV: 10 g/m^2)	Blood, plasma, urine	^19F-NMR	4 Metabolites in blood and plasma (5-fluorouracil, α-fluoro-β-ureidopropionic acid, α-fluoro-β-alanine, 5,6-dihydrofluorouracil); 3 Metabolites in urine (5-fluorouracil, α-fluoro-β-ureidopropionic acid, α-fiuoro-β-alanine)	Not identified	Not evaluated	[^Citation26]
EAPB0203	In vitro	Pooled RLM, DLM	–	HPLC-MS/MS (QqQ and QTOF), ^1H-NMR, ^13C-NMR	4 Metabolites for DLM (EAPB0202, M7, M2, and M1); 6 Metabolites for RLM (EAPB0202, M7, M6, M3, M2, M1)	Hydroxylation (M1-M3, M6, M7); Demethylation (EAPB0202)	Not evaluated	[^Citation28]
EAPB0503 (imiquimod analogs) and EAPB0502 (M’ 7) and EAPB0603 (M’5) (active metabolites of EAPB0503)	In vitro	MLM, RLM, DLM, HLM; Rat, dog, and human hepatocyte	–	LC-ESI-MS/MS	EAPB0503: 6 Metabolites for MLM (M’2-M’7); 4 Metabolites for RLM (M’2, M’4, M’5, M’7); 7 Metabolites for DLM (M’1-M’7); 4 Metabolites for HLM (M’2, M’4, M’5, M’7); 4 Metabolites for rat hepatocyte (M’2, M’4, M’5, and M’7); 5 Metabolites for dog hepatocyte (M’1, M’2, M’4, M’6, M’7); 4 Metabolites for human hepatocyte (M’2, M’4, M’5, M’7) EAPB0502: 2 Metabolites for MLM (M’2 and M’3); 2 Metabolites for RLM (M’2 and M’3); 2 Metabolites for DLM (M’2 and M’3); 1 Metabolite for HLM (M’2); 1 Metabolite for rat hepatocyte (M’3) EAPB0603: 2 Metabolites for MLM (M’1, M’2); 1 Metabolite for RLM (M’2); 2 Metabolites for DLM (M’1, M’2); 1 Metabolite for HLM (M’2); 1 Metabolite for dog hepatocyte (M’1)	O-demethylation (M’5); N-demethylation (M’7); Hydroxylation (M’4, M’6); O- and N-demethylation (M’2); N-demethylation + hydroxylation (M’3); Hydroxylation + O-demethylation (M’1)	Not evaluated	[^Citation29]
E-DE-BPH (E-3,4-bis (4-Ethylphenyl) hex-3-ene: stilbene derivatives)	In vitro	RLM (Aroclor 1254-treated), PLM	–	HPLC-UV, GC-MS, GC-IR	5 Metabolites for Aroclor 1254-treated RLM (M1: 3,4-bis(4-(1-hydroxyethyl) phenyl) hex-3-ene, M2: E-3-(4-acetylphenyl)-4-(4-(1-hydroxyethyl) phenyl) hex-3-ene, M3: E-3,4-bis(4-acetylphenyl) hex-3-ene, M4: E-3-(4-(1-hydroxyethyl) phenyl)-4-(4-ethylphenyl) hex-3-ene, M5: E-3-(4-acetylphenyl)-4- (4-ethylphenyl) hex-3-ene); 4 Metabolites for PLM (M1, M2, M4, M5)	Hydroxylation (M4); Hydroxylation + oxidation (M5); Di-hydroxylation (M1); Hydroxylation + oxidation + hydroxylation or di-hydroxylation + oxidation (M2); Hydroxylation + oxidation + hydroxylation + oxidation or di-hydroxylation + di-oxidation (M3)	Not evaluated	[^Citation30]
2-F-araA (9-β-D-arabinofuranosyl-2-fluoroadenine)	In vivo	Male BDF1 mice (IV: 400 mg/m^2), female beagle dog (IV: 400 mg/m^2), female rhesus monkey (IV: 400 mg/m^2)	Urine, blood	HPLC-MS	1 Metabolite detected in dog blood (9-β-D-arabinofuranosyl hypoxanthine: 2-F-araH); 2 Metabolites for urine of all species (2-fluoroadenine: 2-F-ad, 2-F-araH)	Not identified	2-F-araH: no antitumor activity, no toxicity in BDF1 mice bearing L1210 leukemia cells at 200 mg/kg (IP) for 9 days	[^Citation31]
Flutamide	In vitro	Male human, male dog, and male rat liver microsomes Male pig liver and prostate microsomes	–	LC-ESI-QTOF-MS	Liver microsomes: 1 Metabolites for human (OH-Flu); 4 Metabolites for dog (Flu-1, OH-Flu (2 isoforms), M1, M3); 4 Metabolites for rat (Flu-1, OH-Flu (3 isoforms), M1, M3 (2 isoforms)); 4 Metabolites for pig (Flu-1, OH-Flu (2 isoforms), M1, M3) Prostate microsomes: 2 Metabolites for pig (OH-Flu, Flu-5)	Monohydroxylation (OH-Flu); Di-hydroxylation (M1); Tri-hydroxylation (M3); Sulfation (Flu-3 sulfate); Glucuronidation (Flu-3 glucuronide); Hydroxylation + mercapturic acid conjugation (hydroxyflutamide mercapturic acid); Hydroxylation + glucuronidation (hydroxyflutamide glucuronide); Di-hydroxylation + glucuronidation (M1 glucuronide)	Formation of a mercapturic acid conjugate from flutamide in human urine, suggesting that the reported liver effects of flutamide are due to the molecular mechanism caused by a reactive intermediate	[^Citation32]
	In vivo	Prostate cancer patients) (Oral: 250 mg BID)	Urine		10 Metabolites (Flu-1, Flu-3, Flu-3 sulfate, Flu-3 glucuronide, OH-Flu, M1, M3, hydroxyflutamide mercapturic acid, hydroxyflutamide glucuronide, M1 glucuronide)
4-Hydroxyanisole	In vivo	Malignant melanoma patients (IA: 80 g)	Urine	GC-MS	4 Metabolites (1: hydroquinone, 3: 3.4-dihydroxyanisole, 4: 3-methoxy-4-hydroxyanisol, and 5: 4-hydroxy-3-methoxyanisole)	Methylated metabolites might be conjugated with glucuronic acid or sulphates	Not evaluated	[^Citation33]
Irinotecan	In vitro	HLM, recombinant CYP enzymes (1A1, 1A2, 2C8, 2C9, 3A4, 3A5, and 3A7)	–	HPLC-Spectro-fluorometry, HPLC-MS	4 Metabolites for cells expressing CYP3A4 (M1, NPC, M2, APC); 5 Metabolites for microsomes containing CYP3A4 and CYP3A5 (M1, NPC, M2, APC, M4); 1 Metabolite for cells expressing CYP3A5 (M4); No metabolite for cells expressing CYP2C8, CYP2C9, CYP1A1, CYP1A2, and CYP3A7	Mono-hydroxylation (M1, M2); Loss of terminal piperidine (NPC); Di-oxidation (APC); De-ethylation (M4)	Not evaluated	[^Citation34]
	Phase I and II clinical trials	Cavum carcinoma patient (IV: 300 mg/m^2), brain tumor patient (600 mg/m^2), glioblastoma patients (350 mg/m^2)	Urine		7 Metabolites (SN-38-G, M1, NPC, M2, M3, APC, SN-38)
Ixabepilone	Clinical trial	Cancer patients (IV: 70 mg; 80 nCi)	Plasma, urine, feces	HPLC-AMS, LC-MS	3 Degradants and 4 metabolites for plasma and urine (Deg-1–Deg-3, M8, M16, M19, M41); 3 Degradants and 3 metabolites for feces (Deg-1–Deg-3, M8, M19, M41)	Dehydration (Deg-1-Deg-3); Dehydration + oxygenation (M41); Hydroxylation (M8); Oxygenation + dehydrogenation (M16); Oxygenation + dehydration (M19)	Not evaluated	[^Citation35]
JM216 (bis (acetato) ammine-dichloro (cyclohexylamine) Platinum (IV))	Phase I clinical trial	Cancer patients (PO: 120, 200, 300, 420, 540 mg/m^2)	Plasma	HPLC-MS	6 Platinum metabolites (A, JM383, JM559, D, JM118, F)	Hydrolysis + declorination (JM518, JM559); Di-hydrolysis + di-declorination (JM383); Hydrolysis + declorination +reduction + clorination (JM118); Hydrolysis + declorination + reduction + glutathione conjugation + methylation (A)	JM118: higher cytotoxic activity against 8 human ovarian carcinoma cell lines (HX 62, SKOV-3, CH1, CH1 CISR, 41M, 41M CISR, A2780 A2780 CISR) compared to JM216 and cisplatin JM518 and JM383: similar and less cytotoxic activity to JM216	[^Citation36]
	In vitro	Human plasma	Plasma		5 Platinum metabolites (A, JM383, JM559, JM518, JM118)
K02 (Morpholine-urea-Phe-Hphe-vinylsulfone)	In vitro	HLM, cDNA-expressed CYP3A4	–	HPLC-UV, LC-MS	3 Major metabolites for both (M12, M19, M20)	Hydroxylation	Not evaluated	[^Citation37]
Laromustine	In vitro	RLM, DLM, HLM, MLM	–	HPLC-RD	7 Similar metabolites for all species but in different quantity (C1-C7: C4 = major metabolite)	Demethylsufoxidation.; Hydrolysis; Oxidation	Not evaluated	[^Citation38]
2-Methoxyestradiol	In vitro	Pooled HLM	–	HPLC, HPLC-QqQ -MS	4 Phase I metabolites (A, B, C, D); 2 Phase II metabolites (G1, G2)	Hydroxylation (A, B, C, D); Glucuronidation (G1, G2)	Not evaluated	[^Citation39]
	In vivo	Cancer patients (PO: 800 mg or 2200 mg BID)	Urine		2 Phase II metabolites (G1, G2)	Glucuronidation (G1, G2)
Mitomycin C	In vivo	Murine adenocarcinomas of the colon, MAC 16 (high DT-diaphorase activity) and MAC 26 (low DT-diaphorase activity) bearing mice (Intra tumor: 500 µg)	Tumor	HPLC-UV	4 Metabolites (trans-hydro, cis-hydro, 2,7-diaminomitosene (2,7-DM), decarbamoyl 2,7-DM)	Hydrolysis (trans-hydro, cis-hydro); Reduction (2,7-DM); Reduction + decarbamoyl (decarbamoyl 2,7-DM)	Not evaluated	[^Citation40]
NB-506 (6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(b-D-glucopyranosil) 5H-indolo [2,3-a] pyrrolo [3,4-c] carbazole-5,7(6H)-dione)	In vivo	Male Sprague-Dawley rat (IV: 187.5 mg/m^2 of [^14C] NB-506 (1.85 MBq/kg))	Bile	HPLC-RD-MS, ^1H NMR, ^13C NMR	3 Metabolites (RBM-1, RBM-2, ED501)	Deformyl metabolite (ED501); O-glucuronidation (RBM-1); ED501 + glucuronidation (RBM-2)	Not evaluated	[^Citation41]
9NC (9-nitro-20(S)-camptothecin)	In vivo	Wistar rats (IV: 8 mg/kg)	Bile, urine, feces	LC-IT-MS, LC-QTOF-MS (M2, M5 and M7), ^1H NMR	5 Metabolites for bile (M1, M2, M3: 9-AC, M4: 9-AA-CPT, M5); 3 Metabolites for urine (M1, M3, M6); 3 Metabolites for feces (M4, M6, M7: 9-OH-CPT)	Glucuronidation of 9-OH-CPT (M1); Loss of glutamic acid from M5 (M2); Reduction (M3); Acetylation (M4); Glutathione conjugate of 10-OH-CPT (M5); Mercapturic acid conjugate of 10-OH-CPT (M6); Aglycone of M1 (M7)	Not evaluated	[^Citation42]
NSC 141549 (4ʹ-(9-Acridinylamino) methanesulfon-m-a nisidide (m -AMSA))	In vivo	Male Sprague-Dawley rats (IV: 60 mg/kg and IP: 40 mg/kg)	Plasma (IV), bile (IP)	HPLC-MS	1 Major metabolite for plasma (4-amino-3-methoxymethanesulfonanilide); 1 Major metabolite for bile (9-acridinyl thioether of glutathione)	Methoxylation (4-amino-3-methoxy methanesulfonanilide); Glutathione conjugation (9-acridinyl thioether of glutathione)	Not evaluated	[^Citation43]
NSC 652287 (2,5-bis(5-hydroxymethyl-2-thienyl) furan)	In vitro	Dog liver S9 fraction	–	GC-MS	1 Major metabolite	Methylation or oxidation	Not evaluated	[^Citation44]
NSC 674495 (2-(4-Amino-3-methylphenyl) benzothiazole: DF 203)	In vitro	Breast cancer cell lines (MCF-7, T-47D, and MDA-MB-435) and renal cancer cell lines (TK-10, A498, and CAKI-1)	–	HPLC-spectro-fluorometry, ^1H NMR	1 Major metabolite for sensitive cell lines (T-47D, MDA-MB-435): (6c: 2-(4-amino-3-methylphenyl)-6 hydroxybenzothiazole)	Hydroxylation	6c: low anti-cancer activity against MCF-7 cell lines (IC50>100 M)	[^Citation45]
PAC-1 (4-benzyl-piperazin-1-yl)-acetic acid (3-allyl-2- Hydroxy-benzylidene)-hydrazine	In vivo	Male Wistar rats (PO: 50 mg/kg)	Urine, feces, bile	HPLC-QTOF-MS, HPLC-IT-MS	14 Metabolites for urine (M1-M7, M9-M11, M13-M16); 3 Metabolites for feces (M1, M6, M13); 4 Metabolites for bile (M4, M13, M14, M16)	Debenzylation (M1); Hydroxylation (M2-M6); Dihydroxylation (M8–M12); Carboxylation (M7); Dihydrodiol formation (M13); Glucuronidation (M14); Hydroxylation + glucuronidation (M15-M16)	Not evaluated	[^Citation46]
	In vitro	RLM	–		12 metabolites (M1-M6, M8-M13)
Paclitaxel	In vivo	Ovarian carcinoma patients (IV: 135 mg/m^2)	Plasma, urine	HPLC-MS	2 Metabolites for plasma (P1: 6α-hydroxypaclitaxel, P3: 7-epipaclitaxel); 3 Metabolites for urine (U1: 6α-hydroxypaclitaxel, U2: 10-deacetylpaclitaxel, U4: 7-epipaclitaxel)	Not identified	Not evaluated	[^Citation47]
Paclitaxel	In vitro	Liver microsomes from: Sprague-Dawley & hairless rats (males, females), BALB/c & OF1 mice (males, females), male guinea-pigs, male rabbits, male dogs, male monkeys, and humans	–	HPLC-UV	1 Metabolite for male & female SD and hairless RLM, male & female BALB/c MLM (3′p-hydroxypaclitaxel); 2 Metabolites for male & female OF1 mice & male rabbits (6α hydroxypaclitaxel and 3′p-hydroxypaclitaxel); 2 Metabolites for male dog (6α-hydroxypaclitaxel, 6α,3′p-dihydroxypaclitaxel) liver microsomes; 3 Metabolites in male guinea-pigs, male monkey, human liver microsomes (6α-hydroxypaclitaxel, 3′p-hydroxypaclitaxel, 6α,3′p-dihydroxypaclitaxel)	Mono-hydroxylation (3′p-hydroxypaclitaxel, 6α-hydroxypaclitaxel); Di-hydroxylation (6α,3′p-dihydroxypaclitaxel)	Not evaluated	[^Citation48]
	In vivo	Male Dunkin Hartley albino guinea-pigs (IV: 6 mg/kg)	Bile		2 metabolites (M1: 6α Hydroxypaclitaxel, M2: 3’p-Hydroxypaclitaxel)
Phenylbutyrate	Clinical trial	Human (PO: 0.36 mmol/kg (5 g/75 kg))	Plasma, urine	GC-MS	3 Metabolites for both samples (phenylacetate, phenylacetylglutamine, phenylbutyrylglutamine)	Not identified	Not evaluated	[^Citation49]
Phyllanthoside	In vivo	Male CDF1 mice	Plasma	HPLC-UV	1 Metabolite (M)	Aglycone	M: anticancer activity against human rhabdomyosarcoma cell lines (A204 cell lines) lower than parent compound with IC50 of 24 µM and 0.47 nM	[^Citation50]
Sepin-1	In vitro	MLM, RLM, HLM	–	UHPLC-QTOF-MS	7 Metabolites for all species (M1-M7)	Reduction (M1, M2); Dimer formation (M3-M5); Cysteine conjugation (M6); Glutathione conjugation (M7)	Not evaluated	[^Citation51]
SN30000 (3-(3-Morpholinopropyl)-7,8-dihydro-6H-indeno[5,6-e] [1,2,4] triazine 1,4-dioxide: tirapazamine analog)	In vivo	Female NIH-III mice (IP: 186 mg/kg)	Plasma, liver, HT29 tumor	LC-MS/MS	19 Metabolites for plasma (M1-M19); 16 Metabolites for liver (M3-M7, M9, M10-M19); 19 Metabolites for tumor (M1-M19)	Reduction; Oxidation; Glucuronidation	M14: acute toxicity (hypothermia) similarly to SN30000	[^Citation6]
Tamoxifen	In vivo	Athymic mice (PO and SC: 200 mg/kg/day, 50 mg/kg/day, and 12.5 mg/kg/day), Breast cancer patients (10 mg BID)	Serum	HPLC-UV	2 Metabolites for mouse serum after PO and SC of 200 mg/kg/day and 50 mg/kg/day and patient serum (4-Hydroxytamoxifen and N-desmethyl tamoxifen); Higher level of metabolites with higher doses	Hydroxylation (4-hydroxytamoxifen); N-demethylation (N-desmethyltamoxifen)	Not evaluated	[^Citation52]
Tamoxifen	In vitro	Human liver homogenate, human hepatoblastoma (HepG2) cell lines	–	LC-ESI-MS	6 Metabolites for human liver homogenate (M1-M5, M8); 4 Metabolites for HepG2 (M2-M5)	N-Di-desmethylation (M1); N-Desmethylation (M4); Hydroxylation (M2 and M3); N-oxidation (M5); N-Desmethylation + hydroxylation (M6, M7); N-oxidation + hydroxylation (M8)	Not evaluated	[^Citation53]
	In vivo	Breast cancer patients (PO: 60 mg OD or 30 mg OD > 6 months)	Plasma		8 Metabolites (M1-M8; M8 only in patients who received long term > 6 months)
Tamoxifen	In vivo	Female Rowett athymic nude rats (PO: 5 mg/kg/day or SC: 50 mg)	Serum, liver, lung, retroperitoneal adipose tissue, kidneys, brain, muscle, heart, spleen, stomach, small intestine, uterus tissues		2 Metabolites for all samples except adipose tissue (4-Hydroxytamoxifen, N-Desmethyltamoxifen) after 21 days PO; 4-Hydroxytamoxifen for all samples except adipose tissue and uterus after 33 days PO; N-Desmethyltamoxifen for all samples except adipose tissue after 33 days PO; 2 Metabolites for liver, lung, brain, heart, and kidney (4-Hydroxy tamoxifen and N-Desmethyltamoxifen) after 33 days SC; Level of metabolites detected in SC lower than PO	Hydroxylation (4-Hydroxytamoxifen); Demethylation (N-Desmethyltamoxifen)	Not evaluated	[^Citation54]
Tamoxifen	Clinical trial	Breast cancer patients (PO: 20–40 mg/day)	Plasma	UHPLC-QqQ-Quantum-MS and UHPLC-Exactive Plus Orbitap-MS	40 Metabolites (1–23, 25–27, 29–36, 38, 39, 42–45)	Demethylation + hydroxylation + glucuronidation (1, 9, 13, 19); Hydroxylation + glucuronidation (2, 11, 15, 18); Carboxylation + glucuronidation (3); Di-hydroxylation + oxidation + glucuronidation (4, 21); Di-methylation + tetra-hydroxylation + glucosylation (5); Demethylation + carboxylation (6); Di-hydrodiol (7); Carboxylation (8); Demethylation + hydroxylation (10, 25, 27.32, 44); Hydroxylation (12, 29, 30, 33); Hydroxylation + carboxylation (14); Di-hydroxylation (16, 17, 31); Hydroxylation + sulfation (20); Di-demethylation + tri-hydroxylation + glucoside (22,26); Di-demethylation + hydroxylation (23); E-tamoxifen (34); Di-demethylation (35); Demethylation + desaturation (36); N-demethylation (38); Desaturation (39); Hydroxylation + desaturation (42, 45); Adding NO molecule (43)	Not evaluated	[^Citation55]
TAS-102 (tipiracil hydrochloride (TPI) + trifluridine (FTD))	Clinical trial	Advanced solid tumor patients (PO: 1000 nCi of [^14C]-TPI)	Plasma, urine, feces	HPLC-QqQ-MS	1 Major metabolite for plasma, urine, and feces (6-hydroxyme-thyluracil (6-HMU))	Not identified	Not evaluated	[^Citation56]
		Advanced solid tumor patients (PO: 200 nCi of [^14C]-FTD)			1 Major metabolites for plasma (Trifluoromethyluracil (FTY)); 3 Major metabolites for urine (FTY, FTD Glu U3, FTD Glu U4)	Glucuronidation (FTD Glu U3 and FTD Glu U4); Unidentified (FTY)
TNP-470 (O-(chloroacetyl-carbamoyl) fumagillol)	In vitro	Human hepatocyte, human liver, intestinal, kidney microsomes	–	HPLC-QqQ-MS	6 Metabolites for cultured human hepatocytes (M1-M6: M2 and M5 = predominant metabolites of extracellular and intracellular, respectively); 3 Metabolites for HLM (M1, M2, M4); 2 Metabolites for intestine and kidney microsomes (M2, M4)	Esterase (M4); Esterase + Epoxide hydrolysis (M2)	Not evaluated	[^Citation57]
TW01003 ((3E,6E)-3-Benzylidene-6-[(5- hydroxypyridin-2-yl) methylene] piperazine-2,5-dione)	In vivo	Pig (IV) and male Wistar rats (IV: 7 mg/kg and PO: 36 mg/kg)	Plasma (rat) and urine (pig)	HPLC	1 Metabolite for pig urine (TW-01003 sulfate); 2 Metabolites for rat plasma after IV (TW-01003 sulfate (major), TW-01003 glucuronide); 2 Metabolites after PO (TW-01003 sulfate, TW-01003 glucuronide (major))	Sulfation (TW-01003 sulfate); Glucuronidation (TW-01003 glucuronide)	Not evaluated	[^Citation58]

Abbreviations: AMS, Accelerator Mass Spectrometry; ARC, Accurate Radioisotope Counting; DLM, Dog Liver Microsome; ESI, Electrospray Ionization; GC, Gas Chromatography; HLM, Human Liver Microsome; HPLC, High Performance Liquid Chromatography; IR, Infrared spectroscopy; IP, Intraperitoneal; IT, Ion trap; IV, Intravenous; LC, Liquid Chromatography; MLM, Monkey Liver Microsome; MS, Mass Spectrometry; NMR, Nuclear Magnetic Resonance spectroscopy; PLM, Pig Liver Microsome; PO, Per oral; QqQ, Triple quadrupole; QTOF, Quadrupole Time-of-flight; RD, Radio Detection; RLM, Rat Liver Microsome; SC, Subcutaneous; TIS, Turbo Ion Spray; UHPLC, Ultra-High Performance Liquid Chromatography; UPLC, Ultra Performance Liquid Chromatography; UV, Ultraviolet detection.

Table 2 Metabolism Studies (Metabolite Profiling) of Small Molecules-Targeted Anticancer Drugs

Anticancer Drug	Type of Study	Biochemical Tool/Animal/Human (Route: Dose)	Type of Sample	Analytical Technique	Outcome			Ref.
					Metabolite	Metabolic Pathway	Efficacy/Toxicity of Metabolite
AZD8055	In vitro	RLM	–	UHPLC-IT-MS	5 Metabolites (M1-M5)	Demethylation (M1); Hydroxylation (M2); Oxidation (M3 and M4); Di-oxidation (M4); Morpholine ring opened AZD8055 (M5); Demethylation + glucuronidation (M6); Hydroxylation + glucuronidation (M7); Glucuronidation (M8)	Not evaluated	[^Citation59]
	In vivo	Male Sprague-Dawley rat (PO: 20 mg/kg)	Plasma, urine, feces		8 Metabolites in all samples (M1-M8)
Brivanib	In vitro	Pooled HLM and cytosol, human cDNA-expressed CYP, and human recombinant SULTs	-	HPLC-LTQ-IT-MS	6 Metabolites (M7, M19, M25, M26, M31 M33)	Hydroxylation (M7); Oxidation (M26, M31); Sulfation (M25); Oxidation + sulfation (M19, M33)	Not evaluated	[^Citation60]
EPZ-5676 (Pinometostat)	In vitro	RLM, DLM, HLM, and rat, dog, and human hepatocyte	-	HPLC-RD-IT-TOF-MS	6 Metabolites for RLM (EPZ007769, EPZ007309, M3, M4, M6, M8); 1 Metabolite for DLM (EPZ007769); 5 Metabolites for HLM (EPZ007769, EPZ007309, M3, M4, M6); 7 Metabolites for rat hepatocyte (EPZ007769, EPZ007309, M1a/b, M2, M3, M6, M8); 4 Metabolites for dog hepatocyte (EPZ007769, EPZ007309, M1a/b, M2); 5 Metabolites for human hepatocyte (EPZ007769, EPZ007309, M1a/b, M2, M6)	Mono-hydroxylation (EPZ007769); Mono-hydroxylation + oxidation (EPZ026194); Dealkylation of N-isopropyl (EPZ007309); N-dealkylation + tri-oxidation (M1a/b); N-dealkylation + di-oxidation (M2); N-dealkylation + mono-oxidation (M3); N-dealkylation + keto-oxidation (M4); Mono-oxidation + dehydrogenation (M5); Mono-oxidation (M6 and M7); N-dealkylation + hydroxylation (M8); N-dealkylation (M9, M10 and M11); Oxidative cleavage of ribose ring (M12); N-dealkylation + oxidation (M13)	Not evaluated	[^Citation61]
	In vivo	Sprague– Dawley rats (IV: 30 mg/kg/day (100 µCi/kg)) and Beagle dogs (IV: 10 mg/kg/day (200 µCi/animal))	Plasma, urine, feces, bile (rat and dog)		2 Metabolites for rat plasma (EPZ007769, EPZ026194); 3 Metabolites for rat urine (EPZ007769, EPZ026194, M5); 2 Metabolites for dog urine (EPZ007769, EPZ026194); 4 Metabolites for rat feces (EPZ007769, EPZ026194, M7, M9); 4 Metabolites for dog feces (EPZ007769, EPZ026194, M7, M8); 4 Metabolites for rat bile (EPZ007769, EPZ026194, M5, M6); 2 Metabolites for dog bile (EPZ007769, EPZ026194)
	Phase I clinical trial	Cancer patient (IV: 36 mg/m^2/day)	Plasma, urine		2 Metabolites for plasma (EPZ007769, EPZ007309); 10 Metabolites for urine (EPZ007769, EPZ007309, M1a/b, M2, M8-M13)
HM781-36B (1-[4-[4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy]-piperidin-1-yl] prop-2-en-1-one hydrochloride)	In vivo	Male beagle dogs (PO: 8 mg/kg)	Urine, feces, plasma	HPLC-UV, LC-ESI-IT-MS, LC-QTOF-MS/MS	4 Metabolites for plasma (M1, M2, M8, M10); 3 Metabolites for urine and feces (M1, M2, M10)	Di-hydroxylation (M1); Demethylation (M2); N-Oxidation (M3, M9); Defluorination + hydroxylation (M4); Dechlorination + hydroxylation (M5); Demethylation + di-hydroxylation (M6); N-oxidation + di-hydroxylation (M7); Hydroxylation (M8); Deacryloylpiperideine (M10)	Not evaluated	[^Citation5]
	In vitro	DLM, HLM, Recombinant CYP enzymes (3A4, 2D6, 1A2, 2C9, 2C19, and 2E1)	–		10 Metabolites for HLM (M1-M10); 4 Major metabolites for DLM (M1, M2, M8, M10); 10 Metabolite for rCYP3A4 (M1-M10); 1 Metabolite for rCYP2D6 (M2)
Imatinib	In vitro	Insect-cell microsomes that contained cDNA expressing human CYP isozymes (CYP1A1, 1A2, 1B1, 4F2, 4F3A/B, 3A4)	–	HPLC-LTQ-MS	6 Metabolites (N-demethyl-, Unk#3, Unk#5, Unk#6, Unk#7, Unk#8) for CYP3A4; 4 Metabolites for CYP1A1 (N-demethyl-, Unk#3, Unk#5, Unk#7); 1 Metabolite for 1A2 (7); 2 Metabolites for 1B1 (5 and 7); 2 Metabolites for 4F2 (N-demethyl- and 5); 2 Metabolites for 4F3A and 4F3B (N-demethyl- and 5)	N-demethylation (N-demethyl-); Hydroxylation (Unk#3 and Unk#5); N-oxidation (Unk#6, Unk#7, and Unk#8)	Not evaluated	[^Citation62]
Imatinib	In vitro	HLM	–	HPLC-ESI- QqQ-MS	28 Metabolites (1–17, 19–24, 27–29, 32, 33)	Hydroxylation/N-oxidation (3, 8, 9,11–14, 18, 19, 22–24, 32); Hydroxylation/N-oxidation + N-demethylation (7, 10, 16, 20); Glucuronidation (27–29, 33); Other (2, 6, 31)	Not evaluated	[^Citation63]
	Clinical trial	Cancer patients (PO: 400-800 mg)	Plasma		31 Metabolites (1–14, 16, 18–20, 22–33)
Irosustat	In vitro	RLM, DLM, MLM, HLM, Rats and dogs hepatocytes	–	HPLC-UV, HPLC-MS and ^1H NMR	RLM: 12 Metabolites for male (M7-M11, P-24, M13-M16, M18, 667-coumarin) & female (M7-M11, M13-M16, M18, P36, 667-coumarin); DLM: 14 Metabolites for male & female (P-14, M7-M10, P-23, P-24, M13-M16, M18, P-36, 667-coumarin); MLM: 9 Metabolites for male (P-14, M7-M10, P-24, M13, M14, M16); 8 Metabolites for female (P-14, M7-M10, P-24, M13, M16); HLM: 14 Metabolites for male & female (M7-M11, P-23, P-24, M13-M16, M18, P-36, 667-coumarin); Hepatocytes: 6 Metabolites for male rat (M2, M3, M7, M12, M17, 667-courmarin); 2 Metabolites for male dog (M12, M17); 7 Metabolites for female human (M1, M2, M12, M16, M17, 667-coumarin)	Hydroxylation (M7, M9, M13, M14, M18); Desulfamoylation (667-coumarin); Hydroxylation + desulfamoylation (M8, M15, M16, and P-36); Hydroxylation + desulfamoylation + glucuronidation (M1, M2, and M12); Hydroxylation + desulfamoylation + sulfation (M17); Not identified (M11)	Not evaluated	[^Citation64]
JNJ-38877605	In vitro	Rat, rabbit, dog, monkey, and human hepatocytes and liver subcellular fractions	–	LC-MS	12 Metabolites for all species hepatocyte and liver subcellular fraction (M1-M12)	Hydroxylation (M1, M3); N-demethylation (M2); Oxidation (M4); N-demethylation + hydroxylation (M5-M7); Hydroxylation + glucuronidation (M8); N-demethylation + hydroxylation + glucuronidation (M9 and M11); N-demethylation + glucuronidation (M10); N-demethylation + oxidation + glutathione conjugation (M12)	M1-M5: crystal formation in kidney; M10: renal toxic metabolites in rabbit and human (species-specific toxic metabolite)	[^Citation65]
	In vivo	Rat (PO: 2.5 mg/kg), dog (PO: 2.5 mg/kg), and rabbit (PO: 100 mg/kg)	Plasma, urine, feces		6 Metabolites for rat plasma, urine, feces (M1-M6); 4 Metabolites for dog plasma, urine, feces (M1-M4); 7 Metabolites for rabbit plasma, urine, feces (M2-M7, M10)
	Phase I clinical trial	Cancer patients (PO: 60 mg)	Plasma, urine		4 Metabolites for human plasma and urine (M2, M3, M5, and M10)
Lenvatinib	In vivo	Male Sprague Dawley rats (PO: 30 mg (12.685 MBq)/kg), Cynomolgus monkey (PO: 30 mg (12.685 MBq)/kg), and Solid tumor or lymphoma patients (PO: 24 mg (100 μCi))	Plasma, urine, feces and bile	HPLC-LTQ-IT-MS, HPLC-LTQ-Orbitrap-MS	27 Metabolites for rat (M1-M3, M5, MET5, MET6-MET8, MET10, MET12, MET15, MET17, MET18, MET19a, MET19b, MET20.1, MET21-MET24, MET24.1, MET27, MET29, MET29.1, MET30, MET32, MET34, MET35); 24 Metabolites for monkey (M1-M3, M2ʹ, M3ʹ, M5, MET3, MET4, MET9, MET10, MET13, MET16, MET18, MET20, MET20.1, MET22, MET23, MET24.1, MET26, MET27, MET29.1, MET30, MET32, MET34); 18 Metabolites for human (M1-M3, M2ʹ, M3ʹ, M5, MET3, MET4, MET20.1, MET22, MET24, MET27, MET29.1, MET30-MET32, MET34 MET36)	Oxidation/hydroxylation (M3ʹ, MET34, MET35); Di-oxidation/Di-hydroxylation (MET36); N-oxidation (M3); Dealkylation (M1, M2); Hydrolysis (M5, MET30, MET32); Hydrolysis + oxidation/hydroxylation (MET29); Dealkylation + oxidation/hydroxylation (M2ʹ); Oxidation/hydroxylation + glucuronidation (MET31); Dealkylation + glucuronidation (MET27); Dealkylation + glucuronidation + hydrolysis (MET24); Hydrolysis/O-dearylation (MET29.1); Hydrolysis/O-dearylation + other conjugation (MET20.1, MET24.1); Glutathione/cysteine conjugation and subsequence biodegradation (MET7, MET8, MET10, MET12, MET13, MET15, MET18, MET19b, MET26); Glutathione/cysteine conjugation and subsequence biodegradation + intramolecular arrangement (MET19a and MET21); Glutathione/cysteine conjugation and subsequence biodegradation + intramolecular arrangement + dimerization (MET16, MET17, MET20, MET22, MET23); Glutathione/cysteine conjugation and subsequence biodegradation + intramolecular arrangement + glutathione/cysteine conjugation and subsequence biodegradation (MET3, MET4, MET6, MET9)	Not evaluated	[^Citation66]
Neratinib	In vitro	Rat hepatocytes	-	UHPLC‐DAD, UHPLC-Quadrupole-Orbitrap‐MS	12 Metabolites (M1-M12)	O‐Dealkylation + glutathione conjugation (M1, M2); O‐Dealkylation (M3); Oxygenation + glutathione conjugation (M4, M5); Glutathione conjugation (M6, M7); Oxygenation (M8); N‐Acetylcysteine conjugation (M9, M11); N‐demethylation (M10); N‐oxygenation (M12)	Not evaluated	[^Citation67]
	In vivo	Male Sprague–Dawley rats (PO: 20 mg/kg)	Bile, urine		12 Metabolites for bile (M1-M12); 6 Metabolites for urine (M3 and M8-M12)
ON 013100 ((E)-2,4,6-trimethoxystyryl-3-hydroxy-4-methoxybenzyl sulfone	In vitro	Colon cancer cell lines (drug resistant, colo-205, and drug sensitive, colo-320	–	HPLC-MS, HPLC-MS/MS	E-form and Z-form of glucuronidation of ON 013100 were detected in colo-205 incubation system but not colo-320	Glucuronidation	Not evaluated	[^Citation68]
Osimertinib	In vitro	HLM, MLM	–	UHPLC-MS/MS	7 Metabolites for HLM (DM-1: AZ5104, DM-2:AZ7550, OH-1, OH-2, OH-3, OH-4, OH-5); 4 Metabolites for MLM (DM-1, DM-2, OH-2, OH-4)	N-Demethylation (DM1 and DM-2); Oxidation (OH-1, OH-5); N-oxidation (OH-2, OH-4)	Not evaluated	[^Citation69]
Pimasertib	Clinical trail	Cancer patients (PO: 60 mg)	Plasma, urine, and feces	UPLC-MS	2 Metabolites (M445, M554)	Oxidation (M445); Phosphoethanolamine conjugation (M554)	Not evaluated	[^Citation70]
TKI258 (Dovitinib)	Cohort	Cancer patients (PO: 500 mg)	Plasma, Urine, and Feces	HPLC, LTQ-Orbitrap-MS	3 Metabolites for plasma (M8, M9, M26); 6 Metabolites for urine (M4, M5, M8, M9, M22, M26); 8 Metabolites for feces (M2, M5, M6, M8, M10, M26, M32, M33)	Fluorobenzyl ring hydroxylation (M6, M10); N-demethylation (M8); Piperazine N-oxide (M9); Glucuronidation (M26); Piperazine N-dealkylation (M30); 2 (+O, −2H) on piperazine (M32); (+O, −2H) on piperazine (M33); Fluorobenzyl ring hydroxylation + sulfation (M2 and M5); Fluorobenzyl ring hydroxylation + glucuronidation (M4); N-demethylation + hydroxylation + sulfation (M23)	Not evaluated	[^Citation4]

Abbreviations: CYP, Cytochrome P450; DAD, Diode Array Detection; DLM, Dog Liver Microsome; ESI, Electrospray Ionization; HLM, Human Liver Microsome; HPLC, High Performance Liquid Chromatography; IT, Ion trap; IV, Intravenous; LC, Liquid Chromatography; LTQ, Linear Trap Quadrupole; MS, Mass Spectrometry; MLM, Monkey Liver Microsome; NMR, Nuclear Magnetic Resonance spectroscopy; PO, Per oral; QqQ, Triple quadrupole; QTOF, Quadrupole Time-of-flight; RLM, Rat Liver Microsome; TOF, Time-of-Flight; UHPLC, Ultra-high performance liquid chromatography; UPLC, Ultra Performance Liquid Chromatography; UV, Ultraviolet detection.

Table 3 Metabolism Studies (Metabolite Profiling) of Herb-Derived Compounds with Anticancer Activities

Anticancer Drug	Type of Study	Biochemical Tool/Animal/Human (Route: Dose)	Type of Sample	Analytical Technique	Outcome			Ref.
					Metabolite	Metabolic Pathway	Efficacy/Toxicity of Metabolite
Alantolactone (Inula helenium L.)	In vivo	Male Sprague–Dawley rats (PO: 100 mg/kg)	Urine, feces, bile	UPLC-TOF-MS	11 Metabolites for urine (M1-M5, M10-M11, M14-M16, M18); 10 Metabolites for bile (M1-M4, M8, M12, M25, M33, M43-M44); 38 Metabolites for feces (M1-M13, M17-M25, M27-M31, M33, M35-M44)	Oxidation (M1-M9); Di-oxidation (M10-M11); Demethylation (M12-M13); Demethylation to carboxylic acid (M14-M15); Hydration (M16); Hydrogenation (M17-M18); Addition of H2S (M19-M20); Addition of H2S + oxidation (M21-M23); AL2-S (M24-M25: one sulfur-containing dimer metabolites of alantolactone); AL2-S + oxidation (M27-M31); AL2-SS (M33: two sulfur-containing dimer metabolites of alantolactone); AL2-SS + oxidation (M35-M39); AL2-SSS (M40: three sulfur-containing dimer metabolites of alantolactone); AL2-SSSS (M41: four sulfur-containing dimer metabolites of alantolactone); AL2-SSSSS (M42: five sulfur-containing dimer metabolites of alantolactone); Cysteine conjugation (M43); N-acetylcysteine conjugation (M44)	Not evaluated	[^Citation9]
Astragali Radix water extract (containing calycosin-7-β-glucoside, formononetin, calycosin, ononin, astragaloside IV)	In vivo	Male Sprague–Dawley rats (PO: 4 g/kg and 16 g/kg Astragali Radix water extract)	Plasma	UHPLC-MS/MS	4 Metabolites (calycosin-7-β-glucoside-3ʹ-glucuronide for calycosin-7-β-glucoside, formononetin-3ʹ-glucuronide for formononetin; calycosin-3ʹ-glucuronide for calycosin, daidzein-3ʹ-glucuronide); No metabolites for ononin and astragaloside	Glucuronidation	Not evaluated	[^Citation71]
Calphostin C (Cladosporium cladosporoides)	In vitro	CD-1 MLM	–	LC-MS	1 Metabolite (after incubating liver microsomes with porcine esterase)	Breaking the ester bond	Not evaluated	[^Citation72]
	In vivo	Female CD-1 mice (IP: 40 mg/kg)	Plasma		1 Metabolite
CAT (3,6,7-trimethoxyphenan-throindolizidine (isolated from Tylophora atrofolliculata))	In vivo	Male Wistar rats (PO: 6 mg/kg)	Urine	RRLC-ESI-QTOF-MS	21 metabolites (M1-M21)	Di-demethylation + di-glucuronidation (M1-M3); Di-demethylation + glucuronidation (M4-M9); Demethylation + glucuronidation (M10-M12); Di-demethylation (M13-M15); Demethylation (M16-M18); Oxidation (M19); Hydroxylation (M20-M21)	Not evaluated	[^Citation73]
Dimethoxycurcumin (Curcumin analog)	In vitro	MLM (male CD-1), HLM (CYPream)	–	HPLC-QTRAP, HPLC-QqQ-LIT-MS	8 Metabolites for MLM (369, 371, 383, 385, 399, 401, 559, 561); 7 Metabolites for HLM (369, 383, 385, 399, 401, 559, 561)	Di-O-demethylation (369); Di-O-demethylation + hydrogenation (371); O-demethylation (383); O-demethylation + hydrogenation (385); Hydrogenation (399); Di-hydrogenation (401); O-demethylation + glucuronidation (559); O-demethylation + hydrogenation + glucuronidation (561)	Not evaluated	[^Citation74]
Fisetin (flavonoid compound)	In vivo	Female C57BL/6J mice (IP: 223 mg/kg)	Plasma	HPLC-MS/MS	3 Metabolites (M1, M2, M3: geraldol)	Glucuronidation (M1, M2); Methoxylation (M3)	M3: 2.5 and 1.1-fold higher cytotoxic effect against LLC cell line (Lewis carcinoma) and EAhy 926 cell line (endothelial cell) compared to fisetin, respectively; M3 exhibited 1.5-fold fold higher cytotoxic effect against NIH 3T3 cell line (normal cell)	[^Citation75]
Flavone-8-acetic acid (FAA)	In vitro	HLM, MLM expressing CYP enzyme induced by Aroclor 1245	–	HPLC-UV, HPLC-UV-MS	6 Metabolites for MLM (M1: 3ʹ,4ʹ-dihydrodiol-FAA, M2: 5.6-epoxy-FAA, M3a: 4ʹ-OH-FAA, M3b: 3ʹ-OH-FAA, M3c: 3ʹ,4ʹ-epoxy-FAA, M4: 6-OH-FAA); One human liver microsome (sample 14) produced M3a and another human liver microsome (sample 15) produced 3 metabolites of M1, M3a, M3c: 3ʹ,4ʹ-epoxy-FAA	Epoxide hydrolase reaction (M1); Epoxidation (M2, M3c); Hydroxylation (M3a, M3b, M4)	Interspecies difference metabolism could involve with difference anticancer activity	[^Citation76]
Furanodiene (Rhizoma Curcumae)	In vitro	Rat liver S9, RLM	–	HPLC-ESI-MS, HR-ESI-MS, and ^1H NMR, ^13C NMR, 2D NMR	6 Metabolites for rat liver S9 (M1: 1β,10α,4α,5β-diepoxy-8α-hydroxy-glechoman-8α,12-olide, M2: 2β-hydroxyl-aeruginolactone, M3: 14-hydroxyl-aeruginolactone, M4: 1β,8β-dihydroxyeudesm-4(14),7(11)-dien-8α,12-olide or 1β,8β-dihydroxyeudesm-4,7(11)-dien-8α,12-olide, M5: 1β,8β-dihydroxyeudesm-3,7(11)-dien-8α,12-olide M6: aeruginolactone); 1 Metabolite for RLM (M6)	Oxidation (M6); Oxidation + Hydroxylation (M2, M3); Epoxidation (M1); Epoxidation + new bond formation (M4, M5)	Not evaluated	[^Citation77]
	In vivo	Male Sprague-Dawley Rat (PO: 100 mg/kg)	Bile, urine, feces		6 Metabolites for bile and urine (M1-M6); 1 Metabolite for feces (M6)
(-)-grandisin (extracted from Piper solmsianum)	In vitro	HLM	–	GC-MS and LC-MS	4 Metabolites (M1: 4-O-demethylgrandisin, M2: 4,4′-di-O-demethylgrandisin, M3: 3,4-di-O-demethylgrandisin or 3,5-di-O-demethylgrandisin, M4: 3-O-demethylgrandisin)	Demethylation	Not evaluated	[^Citation2]
Irisflorentin (Belamcanda chinensis)	In vitro	RLM	–	HPLC-UV	7 Metabolites (M1: 6,7-Dihydroxy-5,3′,4′,5′-tetramethoxy isoflavone, M2: Irigenin, M3: 5,7,4′-Trihydroxy-6,3′,5′ trimethoxy isoflavone, M4: 6,7,4′-Trihydroxy-5,3′,5′-trimethoxy isoflavone, M5: 6,7,5′-Trihydroxy-5,3′,4′-trimethoxy isoflavone; M6 and M7: unidentified	Cleavage of methylene acetyl group (M1); Adding of hydroxyl and methoxyl groups (M2-M5)	M1 & M2: 4.6 and 8.4-fold cytotoxic activities against DU145 and 4- and 8.2-fold against MCF-7 cell lines compared with parent compound.	[^Citation78]
Leelamine (bark of pine tree)	In vitro	HLM	–	LC-MS/MS	1 Metabolite in the presence of NADPH generation system	Hydroxylation	Not evaluated	[^Citation7]
	In vivo	Male ICR mice (IP: 10 mg/kg)	Urine, feces		1 Metabolite for urine not in feces
MPD (Methyl protodioscin: isolated from Dioscorea collettii var. hypoglauca))	In vivo	Male Sprague-Dawley rats (PO: 80 mg/kg)	Urine	^1H NMR, ^13C NMR, HRSI-MS	10 Metabolites (M1: Dioscin, M2: pregna-5,16-dien-3β-ol-20-one-O-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→4)]-β-D- glucopyranoside, M3: diosgenin, M4: protobioside, M5: methyl protobioside, M6: 26-O-β-D-glucopyrannosyl (25R)-furan-5-ene-3β,22α, 26-trihydroxy-3-O-α-L-rhamnopy-ranosyl-(1→ 4)-β-D-glucopyranoside, M7: 26-O-β-D-glucopyranosyl (25R)-furan-5-ene-3β,26-dihydroxy-22-methoxy-3-O-α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranoside, M8: prosapogenin A of dioscin, M9: prosapogenin B of dioscin, M10: diosgenin-3-O-β-D-glucopyranoside)	Dealkylation; Dehydration; Oxidation	All metabolites: lower cytotoxic activities against human HepG2, NCI-H460, MCF-7 and HeLa cell lines than parent drug & MPD. However, M1 and M4 exhibited strong anti-cancer activities against HepG2 (M1), NCI-H460 (M1, M4), and HeLa cell lines (M4).	[^Citation79]
Oridonin (ORI) (Diterpinoid of Isodon rubescens)	In vivo	Male Spraque-Dawley rats (PO: 10 mg/kg)	Bile, urine	UPLC-QqQ TOF-MS	17 Metabolites for bile (M1-M4, M6-M18); 10 Metabolites for urine (M1-M6, M12, M14-M16)	Hydroxylation (M1-M3); Ketone Formation (M4); Hydroxylation + hydration (M5); Dehydroxylation (M6-M7); Di-dehydroxylation (M8-M11); Dehydration (M12); Dehydroxylation + dehydration (M13); Didehydroxylation + oxidized to carboxylic acid (M14); Desaturation + oxidized to carboxylic acid (M15); Hydration (M16); Dehydroxylation + glucuronidation (M17, M18)	Not evaluated	[^Citation80]
Quercetin (flavonoid)	In vitro	Human hepatocellular carcinoma cell lines (HepG2)	–	HPLC-RD	1 Metabolite (4)	O-methylation	Not evaluated	[^Citation81]
Trabectedin (ET-743: isolated compound from Ecteinascidia turbinata)	Clinical trial	Cancer patients (IV: 1 mg of trabectedin (2.5 MBq [^14C] trabectedin (70 µCi)))	Urine and feces	HPLC-QqQ-MS and LC-LSC	8 Fractions for urine (U1-U8); 10 Fractions for feces (F1-F10) (U4, F3, and F5: ETM-204; U5 and F6: ETM-217; U6 and F7: ET-759A and ET-731; U7 and F9: ET-745, ETM-259; U8 and F10: ET759B)	Dehydroxylation (ET-745); Dehydroxylation +demethylation (ET-731); Oxidation (ET-759A); Breaking up of the molecule to the individual tetrahydroisoquinoline subunits (ETM259 and ETM204); ETM-259 + acetate ester hydrolysis (ETM217)	Not evaluated	[^Citation82]
Yuanhuapine (Isolated from Daphne genkwa)	In vivo	Male Sprague-Dawley rats (Oral: 5 mg/kg)	Urine	UPLC-QTOF-MS	12 Metabolites (M1-M12)	Hydroxylation (M1-M4); Di-hydroxylation (M5, M6); Tri-hydroxylation (M7); Hydroxylation + glucuronidation (M8); Methylation + di-hydroxylation (M9); (Hydroxylation + methylation) + (hydroxylation + glucuronidation) (M10); Reduction + 2(Cysteine conjugation) (M11); Hydration + (S-Cysteine conjugation) (M12)	Not evaluated	[^Citation3]
Ziyuglycoside II (Sanguisorba officinalis L.)	In vitro	Rat liver homogenate	–	LC-QTOF-MS	16 metabolites (H-M1-H-M16)	Glucuronidation (H-M1); Glucose conjugation (H-M2-H-M4); Dehydration + glucuronidation (H-M5); Formolation of ziyuglycoside II (adding CO: H-M6); Oxidation + reduction (H-M7); Dehydrogenation (H-M8); Demethylation (H-M9); Dehydration (H-M10, H-M11); Dearabinosylation + oxidation (H-M12, H-M13); Dearabinosylation (H-M14); Dearabinosylation + reduction (H-M15, H-M16)	Not evaluated	[^Citation83]
	In vivo	Male Sprague-Dawley rats (Oral: 50 mg/kg)	Urine, feces	UFLC-QTOF-MS	10 Metabolites for urine (U-M1-U-M10); 10 Metabolites for feces (F-M1 and F-M10)	Glucuronidation + glycosylation (U-M1); Glucuronidation + deglycosylation + decarboxylation + dihydroxylation (U-M2); U-M2 + deoxidation + methylation (U-M3); Glucuronidation + loss of C2H2O (U-M4); U-M4 + deoxidation + methylation (U-M5); Decarboxylation (U-M7); Glucosylation (U-M6); Dearabinosylation (U-M9 and F-M9); Dearabinosylation + oxidization (U-M8, F-M5, F-M6); Dearabinosylation +dehydrogenation (U-M10); Oxidation (F-M1); F-M1 + dehydrogenation (F-M2); Dehydration (F-M3and F-M4); Dearabinosylation + loss of CO (F-M7); Dearabinosylation + demethylation (F-M8); F-M9 + dehydrogenation (F-M10)

Abbreviations: ESI, Electrospray Ionization; GC, Gas Chromatography; HLM, Human Liver Microsome; HPLC, High Performance Liquid Chromatography; HR, High Resonance; HRSI, High Resolution Single Ion; IP, Intraperitoneal; IV, Intravenous; LC, Liquid Chromatography; MS, Mass Spectrometry; MLM, Monkey Liver Microsome; NMR, Nuclear Magnetic Resonance spectroscopy; PO, Per oral; QqQ, Triple quadrupole; LIT, Linear Ion Trap; LSC, Liquid Scintillation Counting; QTOF, Quadrupole Time-of-flight; QTRAP, Linear ion trap Triple Quadrupole; RD, Radio Detection; RLM, Rat Liver Microsome; RRLC, Rapid Resonance Liquid Chromatography; TIS, Turbo Ion Spray; TOF, Time-of-Flight; UHPLC, Ultra-high performance liquid chromatography; UPLC, Ultra Performance Liquid Chromatography; UV, Ultraviolet detection.

Table 4 Activities of Conventional Anticancer Drugs, Synthetic Anticancer Candidates, Small Molecules Targeted Therapy, Herb-Derived Compounds

Compounds	References	Activity
Conventional anticancer drugs
AM6-36 (3-amino-6-(3′-aminopropyl)-5H-indeno[1,2-c] isoquinoline-5,11-(6H) dione)	[^Citation13]	Antiproliferation (Breast cancer cell line (MCF-7))
ARQ 501 (synthetic β-lapachone)	[^Citation15]	Anticancer (Pancreatic, head and neck cancer, and leiomyosarcoma)
Cabazitaxel	[^Citation16]	Anticancer (Prostate cancer)
Capecitabine	[^Citation17]	Anticancer (Colorectal cancer)
Carbendazim	[^Citation18]	Apoptotic induction, Antitumor (Solid tumor)
CI-941(losoxantrone)	[^Citation19]	Anticancer (Breast and prostate cancers)
CP-31398 (N’-[2-[2-(4-methoxyphenyl) ethenyl)-4-quinazolinyl]-N, N-dimethyl-1,3-propanediamine Dihydrochloride)	[^Citation84,Citation85]	Antiproliferative (Colon cancer (DLD1) and lung cancer (H460) and intestinal tumor cells)
CPA (Cyproterone acetate)	[^Citation22]	Anticancer (Prostate cancer)
Cisplatin	[^Citation20]	Anticancer (Testicular, ovarian, bladder, cervical, esophageal, small cell lung, head and neck cancers)
Crisnatol	[^Citation23]	Antitumor (Hepatoma)
Cyclophosphamide	[^Citation24,Citation86]	Anticancer (Leukemia, lymphoma, breast, lung, prostate, and ovarian cancers)
DFS (Trans-2,6-difluoro-4′-(N, N-dimethylamino) stilbene: Stilbene analog)	[^Citation25]	Antitumor (Colorectal cancer)
5ʹ-dFUrd and 5ʹ-dFUR (5ʹ-deoxy-5-fluorouridine)	[^Citation26,Citation27]	Anticancer (Gastric, colorectal, and breast cancer)
EAPB0203	[^Citation28]	Antitumor (Melanoma, T lymphoma, colon, and breast cancers)
EAPB0503	[^Citation29]	Antitumor (Melanoma, T lymphoma, and colon cancer)
E-DE-BPH (E-3,4-bis (4-Ethylphenyl) hex-3-ene: stilbene derivatives)	[^Citation30]	Anticancer
2-F-araA (9-β-D-arabinofuranosyl-2-fluoroadenine)	[^Citation31]	Antitumor (Leukemia)
Flutamide	[^Citation32]	Antiandrogen (Prostate cancer)
4-Hydroxyanisole	[^Citation33]	Anticancer (Malignant melanoma)
Irinotecan	[^Citation34]	Anticancer (Colon and lung cancer)
Ixabepilone	[^Citation87]	Anticancer (Metastatic breast cancer)
JM216	[^Citation36]	Antitumor (Human ovarian carcinoma cell model)
KO2 (Morpholine-urea-Phe-Hphe-vinylsulfone)	[^Citation37]	Inhibit cancer progress by inhibiting potent cysteine protease
Laromustine	[^Citation38]	Anticancer (Leukemia)
2-Methoxyestradiol	[^Citation39]	Anticancer (Metastatic breast cancer, prostate cancer, and various tumors)
Mitomycin C	[^Citation88]	Anticancer (Bladder, colon, and breast cancers)
NB-506 (6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(b-D-glucopyranosil) 5H-indolo [2,3-a]pyrrolo [3,4-c]carbazole-5,7(6H)-dione)	[^Citation41,Citation89]	Antitumor (lung and colon cancers, and metastatic cells)
9NC (9-Nitro-20(S)-camptothecin)	[^Citation90]	Anticancer (Ovarian, tubal, and peritoneal cancer)
NSC 141549 (4ʹ-(9-Acridinylamino) methanesulfon-rn-anisidide (rn -AMSA))	[^Citation43]	Antitumor (L1210 leukemia and Lewis lung carcinoma)
NSC 652287 (2,5-bis(5-hydroxymethyl-2-thienyl) furan)	[^Citation44,Citation91]	Antiproliferative (renal carcinoma cells)
NSC 674495 (2-(4-Amino-3-methylphenyl) benzothiazole: DF 203)	[^Citation45]	Antitumor (Breast cancer (MCF-7 and MDA 468) cells models)
PAC-1 (4-benzyl-piperazin-1-yl)-acetic acid (3-allyl-2- Hydroxy-benzylidene)-hydrazine	[^Citation46,Citation92]	Antitumor (colon cancer cell models)
Paclitaxel	[^Citation47]	Anticancer (Breast, lung, head, neck, and ovarian cancers)
Phenylbutyrate	[^Citation93]	Antitumor (Human prostate cancer, hepatocarcinoma and hepatoblastoma models), Anticancer (Acute myelogenous leukemia)
Phyllanthoside	[^Citation50]	Antitumor (BI6 melanoma and P388 leukemia)
Sepin-1	[^Citation51]	Antiproliferative (Breast cancer, leukemia, and neuroblastoma), Antitumor (breast carcinoma), Apoptotic induction
SN30000 (3-(3-Morpholinopropyl)-7,8-dihydro-6H-indeno[5,6-e] [1,2,4] triazine 1.4-dioxide: tirapazamine analog)	[^Citation6,Citation94]	Antiproliferative (Human colon cancer (HT29) and cervical (SiHa) cancer cells), Antitumor (HT29 and SiHa cancer cells models)
Tamoxifen	[^Citation54,Citation55]	Antiestrogen (Breast cancer)
TAS-102 (tipiracil hydrochloride (TPI) + trifluridine (FTD))	[^Citation56]	Anticancer (Metastatic colorectal cancer)
TNP-470 (O-(chloroacetyl-carbamoyl) fumagillol)	[^Citation57]	Antitumor (B16 BL6 melanoma, M 5076 reticulum cell sarcoma, Lewis lung carcinoma, Walker 256 carcinoma), Anticancer, Antiangiogenesis
TW01003 ((3E,6E)-3-Benzylidene-6-[(5-hydroxypyridin-2-yl) methylene] piperazine-2,5-dione)	[^Citation58]	Antitumor, Antiangiogenesis
Small molecules-targeted anticancer drugs
AZD8055	[^Citation59]	Antiproliferation, Apoptotic induction, and Migration reduction (Leukemia, cervical, breast cancer, and laryngeal carcinoma)
Brivanib	[^Citation60,Citation95]	Anticancer (Hepatocellular carcinoma)
EPZ-5676 (pinometostat)	[^Citation61]	Anticancer (Leukemia)
HM781-36B (1-[4-[4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy]-piperidin-1-yl] prop-2-en-1-one hydrochloride)	[^Citation5]	Anticancer (Advanced solid tumors i.e. non-small-cell lung cancer (NSCLC) patients with EGFR mutation (T790M), breast, and gastric cancer)
Imatinib	[^Citation62,Citation63]	Anticancer (Chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST))
Irosustat	[^Citation64]	Antitumor (Breast cancer model), Anticancer (Breast cancer)
JNJ-38877605	[^Citation65]	Antitumor (Prostate, non-small-cell lung, and gastric cancer and glioblastoma cells models)
Lenvatinib	[^Citation66]	Anticancer (Hepatocellular carcinoma, melanoma, renal carcinoma, non-small-cell lung carcinoma, glioblastoma multiforme, ovarian and endometrial carcinoma)
Neratinib	[^Citation67]	Anticancer (Breast cancer)
ON 013100 ((E)-2,4,6-trimethoxystyryl-3-hydroxy-4-methoxybenzyl sulfone (Kinase inhibitor))	[^Citation68]	Anticancer (Lymphoma and acute lymphoid leukemia)
Osimertinib	[^Citation69]	Anticancer (Non–small cell lung cancer)
Pimasertib	[^Citation70]	Anticancer (Non-small cell lung, colorectal cancer, and head and neck squamous cell carcinoma)
TKI258 (dovitinib)	[^Citation96]	Anticancer (Renal cell carcinoma, advanced breast cancer, relapsed multiple myeloma and urothelial cancer)
Herb-derived compounds
Alantolactone (Inula helenium L.)	[^Citation9]	Antitumor (Liver cancer cells model)
Astragali Radix (water extract)	[^Citation71]	Apoptotic induction
Calphostin C (Cladosporium cladosporoides)	[^Citation72]	Antitumor (Leukemia model), apoptotic induction
CAT (3,6,7-trimethoxyphenan-throindolizidine (isolated from Tylophora atrofolliculata))	[^Citation73]	Antitumor
Dimethoxycurcumin (Curcumin analog)	[^Citation74]	Antiproliferation and apoptosis induction (Human colon (HCT116) cancer cells model)
Fisetin (flavonoid compound)	[^Citation75]	Antiproliferation (Human leukemia (HL60), breast (MCF7), colon (HT29), liver (SK-HEP-1, Caco-2), neuroblastoma (SHEP, WAC-2), prostate (LNCaP, PC3) cells models)
Flavone-8-acetic acid (FAA)	[^Citation76]	Antitumor (Solid murine and human tumor cells models)
Furanodiene (Rhizoma Curcumae)	[^Citation77]	Antiproliferation (Human cervical (Hela), laryngeal (Hep-2), Leukemia (HL-60), prostate (PC3), and gastric (SGC-7901) cancer and fibrosarcoma (HT-1080) cells models)
(-)-grandisin (extracted from Piper solmsianum)	[^Citation2,Citation97]	Antitumor (Ehrlich Ascites Tumoral (EAT) models)
Irisflorentin (Belamcanda chinensis)	[^Citation78]	Antiproliferation (prostate (DU145) and breast (MCF-7) cancer models)
Leelamine (bark of pine tree)	[^Citation7]	Antiproliferation by apoptotic induction (breast cancer model),
MPD (Methyl protodioscin: isolated from Dioscorea collettii var. hypoglauca))	[^Citation79]	Antiproliferation (Leukemia and solid tumors models)
Oridonin (ORI) (Diterpinoid of Isodon rubescens)	[^Citation80]	Antiproliferation (Murine and human melanoma cells models)
Quercetin (flavonoid)	[^Citation98]	Antiproliferative by apoptotic induction (Colon carcinoma (CT-26), prostate adenocarcinoma (LNCaP), lymphoblastic leukemia MOLT-4 T-cells, and human lymphoid (Raji) cell models), Antitumor (breast (MCF-7) and colon carcinoma (CT-26) models)
Trabectedin (ET-743: isolated compound from Ecteinascidia turbinata)	[^Citation82]	Anticancer (Soft tissue sarcoma, ovarian and breast cancer)
Yuanhuapine (Isolated from Daphne genkwa)	[^Citation3]	Antiproliferative (Murine lymphocytic leukemia (P-338), Human lung carcinoma (A-549) cells models)
Ziyuglycoside II (Sanguisorba officinalis L.)	[^Citation83]	Antiproliferative (Gastric and breast carcinoma)

Figure 1 Flow diagram summarizing steps for exclusion and inclusion of the research articles included in the analysis.

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