4,109
Views
30
CrossRef citations to date
0
Altmetric
Review Article

Saikosaponin D: review on the antitumour effects, toxicity and pharmacokinetics

, , , , &
Pages 1478-1487 | Received 02 May 2021, Accepted 07 Oct 2021, Published online: 29 Oct 2021

References

  • Abe H, Sakaguchi M, Konishi H, Tani T, Arichi S. 1978. The effects of saikosaponins on biological membranes. 1. The relationship between the structures of saikosaponins and haemolytic activity. Planta Med. 34(2):160–166.
  • Ashour ML, Wink M. 2011. Genus Bupleurum: a review of its phytochemistry, pharmacology and modes of action. J Pharm Pharmacol. 63(3):305–321.
  • Bar-Zeev M, Livney YD, Assaraf YG. 2017. Targeted nanomedicine for cancer therapeutics: towards precision medicine overcoming drug resistance. Drug Resist Updat. 31:15–30.
  • Bu S, Xu J, Sun J. 2000. Effect of saikosaponin-D on up-regulating GR mRNA expression and inhibiting cell growth in human leukemia cells. Zhongguo Zhong Xi Yi Jie He Za Zhi. 20(5):350–352.
  • Cai C, Zhang H, Ou Y, Jiang Y, Zhong D, Qi H, Dang Q. 2017. Saikosaponin-D suppresses cell growth in renal cell carcinoma through EGFR/p38 signaling pathway. Neoplasma. 64(4):518–525.
  • Chen L, Zhang F, Kong D, Zhu X, Chen W, Wang A, Zheng S. 2013. Saikosaponin D disrupts platelet-derived growth factor-β receptor/p38 pathway leading to mitochondrial apoptosis in human LO2 hepatocyte cells: a potential mechanism of hepatotoxicity. Chem Biol Interact. 206(1):76–82.
  • Cheng J, Fan XM. 2013. Role of cyclooxygenase-2 in gastric cancer development and progression. World J Gastroenterol. 19(42):7361–7368.
  • Cragg GM, Newman DJ. 2005. Plants as a source of anti-cancer agents. J Ethnopharmacol. 100(1–2):72–79.
  • Du JR, Long FY, Chen C. 2014. Research progress on natural triterpenoid saponins in the chemoprevention and chemotherapy of cancer. Enzymes. 36:95–130.
  • Efferth T, Li PC, Konkimalla VS, Kaina B. 2007. From traditional Chinese medicine to rational cancer therapy. Trends Mol Med. 13(8):353–361.
  • Elmeliegy M, Vourvahis M, Guo C, Wang DD. 2020. Effect of p-glycoprotein (p-gp) inducers on exposure of p-gp substrates: review of clinical drug-drug interaction studies. Clin Pharmacokinet. 59(6):699–714.
  • Fu R, Zhang L, Li Y, Li B, Ming Y, Li Z, Xing H, Chen J. 2020. Saikosaponin D inhibits autophagosome-lysosome fusion and induces autophagy-independent apoptosis in MDA-MB-231 breast cancer cells. Mol Med Rep. 22(2):1026–1034.
  • Gao T, Zhao P, Yu X, Cao S, Zhang B, Dai M. 2019. Use of saikosaponin D and JNK inhibitor SP600125, alone or in combination, inhibits malignant properties of human osteosarcoma U2 cells. Am J Transl Res. 11(4):2070–2080.
  • Gezici S, Şekeroğlu N. 2019. Current perspectives in the application of medicinal plants against cancer: novel therapeutic agents. Anticancer Agents Med Chem. 19(1):101–111.
  • Giroux-Leprieur E, Costantini A, Ding VW, He B. 2018. Hedgehog signaling in lung cancer: from oncogenesis to cancer treatment resistance. IJMS. 19(9):2835.
  • Guengerich FP, Waterman MR, Egli M. 2016. Recent structural insights into cytochrome P450 function. Trends Pharmacol Sci. 37(8):625–640.
  • Hashemi Goradel N, Najafi M, Salehi E, Farhood B, Mortezaee K. 2019. Cyclooxygenase-2 in cancer: a review. J Cell Physiol. 234(5):5683–5699.
  • He S, Lu G, Hou H, Zhao Z, Zhu Z, Lu X, Chen J, Wang Z. 2014. Saikosaponin-D suppresses the expression of cyclooxygenase-2 through the phospho-signal transducer and activator of transcription 3/hypoxia-inducible factor-1α pathway in hepatocellular carcinoma cells. Mol Med Rep. 10(5):2556–2562.
  • He Y, Hu Z, Li A, Zhu Z, Yang N, Ying Z, He J, Wang C, Yin S, Cheng S. 2019. Recent advances in biotransformation of saponins. Molecules. 24:2365.
  • Hsu YL, Kuo PL, Chiang LC, Lin CC. 2004. Involvement of p53, nuclear factor kappaB and Fas/Fas ligand in induction of apoptosis and cell cycle arrest by saikosaponin D in human hepatoma cell lines. Cancer Lett. 213(2):213–221.
  • Hsu YL, Kuo PL, Lin CC. 2004. the proliferative inhibition and apoptotic mechanism of saikosaponin D in human non-small cell lung cancer A549 cells. Life Sci. 75(10):1231–1242.
  • Hu SC, Lai YC, Lin CL, Tzeng WS, Yen FL. 2019. Inclusion complex of saikosaponin-D with hydroxypropyl-β-cyclodextrin: improved physicochemical properties and anti-skin cancer activity. Phytomedicine. 57:174–182.
  • Hu SC, Lee IT, Yen MH, Lin CC, Lee CW, Yen FL. 2016. Anti-melanoma activity of Bupleurum chinense, Bupleurum kaoi and nanoparticle formulation of their major bioactive compound saikosaponin-D. J Ethnopharmacol. 179:432–442.
  • Huang W, Sun R. 2010. Study on hepatotoxicity on rats caused by crude extracts of total saikosaponins and correlation with oxidative damage mechanism. Zhongguo Zhong Yao Za Zhi. 35:1745–1749.
  • Hussain S, Singh A, Nazir SU, Tulsyan S, Khan A, Kumar R, Bashir N, Tanwar P, Mehrotra R. 2019. Cancer drug resistance: a fleet to conquer. J Cell Biochem. 120(9):14213–14225.
  • Ikegami F, Fujii Y, Ishihara K, Satoh T. 2003. Toxicological aspects of Kampo medicines in clinical use. Chem Biol Interact. 145(3):235–250.
  • Jiang H, Yang L, Hou A, Zhang J, Wang S, Man W, Zheng S, Yu H, Wang X, Yang B, et al. 2020. Botany, traditional uses, phytochemistry, analytical methods, processing, pharmacology and pharmacokinetics of Bupleuri Radix: a systematic review. Biomed Pharmacother. 131:110679.
  • Katz OB, Shaked Y. 2015. Host effects contributing to cancer therapy resistance. Drug Resist Updat. 19:33–42.
  • Kiess TO, Kockskämper J. 2019. SERCA activity controls the systolic calcium increase in the nucleus of cardiac myocytes. Front Physiol. 10:56.
  • King FW, Fong S, Griffin C, Shoemaker M, Staub R, Zhang YL, Cohen I, Shtivelman E. 2009. Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress. PLoS One. 4(9):e7283.
  • Kirtane AR, Kalscheuer SM, Panyam J. 2013. Exploiting nanotechnology to overcome tumor drug resistance: challenges and opportunities. Adv Drug Deliv Rev. 65(13–14):1731–1747.
  • Lai M, Ge Y, Chen M, Sun S, Chen J, Cheng R. 2020. Saikosaponin D inhibits proliferation and promotes apoptosis through activation of MKK4-JNK signaling pathway in pancreatic cancer cells. Onco Targets Ther. 13:9465–9479.
  • Li C, Guan X, Xue H, Wang P, Wang M, Gai X. 2017. Reversal of P-glycoprotein-mediated multidrug resistance is induced by saikosaponin D in breast cancer MCF-7/adriamycin cells. Pathol Res Pract. 213(7):848–853.
  • Li C, Xue HG, Feng LJ, Wang ML, Wang P, Gai XD. 2017. The effect of saikosaponin D on doxorubicin pharmacokinetics and its MDR reversal in MCF-7/adr cell xenografts. Eur Rev Med Pharmacol Sci. 21(19):4437–4445.
  • Li DQ, Wu J, Liu LY, Wu YY, Li LZ, Huang XX, Liu QB, Yang JY, Song SJ, Wu CF. 2015. Cytotoxic triterpenoid glycosides (saikosaponins) from the roots of Bupleurum chinense. Bioorg Med Chem Lett. 25(18):3887–3892.
  • Li H, Tang Y, Wang Y, Wei W, Yin C, Tang F. 2020. Effects of saikosaponin D on CYP1A2 and CYP2D6 in HepaRG Cells. Drug Des Devel Ther. 14:5251–5258.
  • Li H, Tang Y, Wei W, Yin C, Tang F. 2021. Effects of saikosaponin-D on CYP3A4 in HepaRG cell and protein-ligand docking study. Basic Clin Pharmacol Toxicol. 128(5):661–668.
  • Li X, Li X, Huang N, Liu R, Sun R. 2018. A comprehensive review and perspectives on pharmacology and toxicology of saikosaponins. Phytomedicine. 50:73–87.
  • Li Y, Cai T, Zhang W, Zhu W, Lv S. 2017. Effects of saikosaponin D on apoptosis in human U87 glioblastoma cells. Mol Med Rep. 16(2):1459–1464.
  • Lin HJ, Kao ST, Siao YM, Yeh CC. 2015. The Chinese medicine Sini-San inhibits HBx-induced migration and invasiveness of human hepatocellular carcinoma cells. BMC Complement Altern Med. 15:348.
  • Liu J, Xue Y, Sun J, Fu R, Ren S, Zhang Z, Song R. 2019. Pharmacokinetics and oral bioavailability studies of three saikogenins in rats using a validated UFLC-MS/MS method. J Chromatogr B Analyt Technol Biomed Life Sci. 1124:265–272.
  • Liu RY, Li JP. 2014. Saikosaponin-D inhibits proliferation of human undifferentiated thyroid carcinoma cells through induction of apoptosis and cell cycle arrest. Eur Rev Med Pharmacol Sci. 18(17):2435–2443.
  • Lorent JH, Quetin-Leclercq J, Mingeot-Leclercq MP. 2014. The amphiphilic nature of saponins and their effects on artificial and biological membranes and potential consequences for red blood and cancer cells. Org Biomol Chem. 12(44):8803–8822.
  • Lv L, Huang W, Yu X, Ren H, Sun R. 2009. Comparative research of different Bupleurum chinense composition to influence of hepatotoxicity of rats and oxidative damage mechanism. Zhongguo Zhong Yao Za Zhi. 34(18):2364–2368.
  • Mahboubi Rabbani SMI, Zarghi A. 2019. Selective COX-2 inhibitors as anticancer agents: a patent review (2014-2018). Expert Opin Ther Pat. 29(6):407–427.
  • Maik-Rachline G, Lifshits L, Seger R. 2020. Nuclear p38: roles in physiological and pathological processes and regulation of nuclear translocation. IJMS. 21(17):6102.
  • Martínez-Limón A, Joaquin M, Caballero M, Posas F, de Nadal E. 2020. The p38 pathway: from biology to cancer therapy. IJMS. 21(6):1913.
  • Meng J, Yao R, Chen X, Yang X, Li Z. 2012. Advances in studies on classification of Bupleurum. Zhongguo Zhong Yao Za Zhi. 37(11):1523–1526.
  • Meselhy M. 1999. Human intestinal bacteria responsible for the metabolism of saikosaponins. J Trandition Med. 17:1–11.
  • Möbius C, Stein HJ, Spiess C, Becker I, Feith M, Theisen J, Gais P, Jütting U, Siewert JR. 2005. COX2 expression, angiogenesis, proliferation and survival in Barrett's cancer. Eur J Surg Oncol. 31(7):755–759.
  • Mollinedo F, Gajate C. 2020. Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy: thematic review series: biology of lipid rafts. J Lipid Res. 61(5):611–635.
  • Nose M, Amagaya S, Ogihara Y. 1989. Effects of saikosaponin metabolites on the hemolysis of red blood cells and their adsorbability on the cell membrane. Chem Pharm Bull (Tokyo)). 37(12):3306–3310.
  • Platanias LC. 2003. The p38 mitogen-activated protein kinase pathway and its role in interferon signaling. Pharmacol Ther. 98(2):129–142.
  • Prueksaritanont T, Chu X, Gibson C, Cui D, Yee KL, Ballard J, Cabalu T, Hochman J. 2013. Drug-drug interaction studies: regulatory guidance and an industry perspective. Aaps J. 15(3):629–645.
  • Qin T, Fu X, Yu J, Zhang R, Deng X, Fu Q, Ma Z, Ma S. 2019. Modification of GSK3β/β-catenin signaling on saikosaponins-D-induced inhibition of neural progenitor cell proliferation and adult neurogenesis. Toxicology. 424:152233.
  • Qin T, Yuan Z, Yu J, Fu X, Deng X, Fu Q, Ma Z, Ma S. 2020. Saikosaponin-D impedes hippocampal neurogenesis and causes cognitive deficits by inhibiting the survival of neural stem/progenitor cells via neurotrophin receptor signaling in mice. Clin Transl Med. 10(8):e243.
  • Ren M, McGowan E, Li Y, Zhu X, Lu X, Zhu Z, Lin Y, He S. 2019. Saikosaponin-D suppresses COX2 through p-STAT3/C/EBPβ signaling pathway in liver cancer: a novel mechanism of action. Front Pharmacol. 10:623.
  • Sanchez-Prieto R, Rojas JM, Taya Y, Gutkind JS. 2000. A role for the p38 mitogen-acitvated protein kinase pathway in the transcriptional activation of p53 on genotoxic stress by chemotherapeutic agents. Cancer Res. 60(9):2464–2472.
  • Shaheen U, Ragab EA, Abdalla AN, Bader A. 2018. Triterpenoidal saponins from the fruits of Gleditsia caspica with proapoptotic properties. Phytochemistry. 145:168–178.
  • Shimizu K, Amagaya S, Ogihara Y. 1985. Structural transformation of saikosaponins by gastric juice and intestinal flora. J Pharmacobiodyn. 8(9):718–725.
  • Tang C, Fu Q, Chen X, Hu Y, Renaud H, Ma C, Rao T, Chen Y, Tan Z, Klaassen CD, et al. 2020. The biotransformation of Bupleuri Radix by human gut microbiota. Xenobiotica. 50(9):1011–1022.
  • Tang JC, Long F, Zhao J, Hang J, Ren YG, Chen JY, Mu B. 2019. The effects and mechanisms by which saikosaponin-D enhances the sensitivity of human non-small cell lung cancer cells to gefitinib. J Cancer. 10(26):6666–6672.
  • Tian YD, Lin S, Yang PT, Bai MH, Jin YY, Min WL, Ma HB, Wang BF. 2019. Saikosaponin-D increases the radiosensitivity of hepatoma cells by adjusting cell autophagy. J Cancer. 10(20):4947–4953.
  • Trempolec N, Dave-Coll N, Nebreda AR. 2013. Snapshot: p38 MAPK substrates. Cell. 152(4):924–924.e921.
  • Tsai YJ, Chen IL, Horng LY, Wu RT. 2002. Induction of differentiation in rat C6 glioma cells with saikosaponins. Phytother Res. 16(2):117–121.
  • Tsuyoshi H, Wong VKW, Han Y, Orisaka M, Yoshida Y, Tsang BK. 2017. Saikosaponin-D, a calcium mobilizing agent, sensitizes chemoresistant ovarian cancer cells to cisplatin-induced apoptosis by facilitating mitochondrial fission and G2/M arrest. Oncotarget. 8(59):99825–99840.
  • Waheed A, Barker J, Barton SJ, Owen CP, Ahmed S, Carew MA. 2012. A novel steroidal saponin glycoside from Fagonia indica induces cell-selective apoptosis or necrosis in cancer cells. Eur J Pharm Sci. 47(2):464–473.
  • Wang BF, Dai ZJ, Wang XJ, Bai MH, Lin S, Ma HB, Wang YL, Song LQ, Ma XL, Zan Y, et al. 2013. Saikosaponin-D increases the radiosensitivity of SMMC-7721 hepatocellular carcinoma cells by adjusting the G0/G1 and G2/M checkpoints of the cell cycle. BMC Complement Altern Med. 13:263.
  • Wang BF, Lin S, Bai MH, Song LQ, Min WL, Wang M, Yang P, Ma HB, Wang XJ. 2014. Effects of SSD combined with radiation on inhibiting SMMC-7721 hepatoma cell growth. Med Sci Monit. 20:1340–1344.
  • Wang J, Qi H, Zhang X, Si W, Xu F, Hou T, Zhou H, Wang A, Li G, Liu Y, et al. 2018. Saikosaponin D from Radix Bupleuri suppresses triple-negative breast cancer cell growth by targeting β-catenin signaling . Biomed Pharmacother. 108:724–733.
  • Wang P, Ren J, Tang J, Zhang D, Li B, Li Y. 2010. Estrogen-like activities of saikosaponin-D in vitro: a pilot study. Eur J Pharmacol. 626(2–3):159–165.
  • Wang Q, Zheng X, Yang L, Shi F, Gao L, Zhong Y, Sun H, He F, Lin Y, Wang X. 2010. Reactive oxygen species-mediated apoptosis contributes to chemosensitization effect of saikosaponins on cisplatin-induced cytotoxicity in cancer cells. J Exp Clin Cancer Res. 29:159.
  • Wang S, Zhang Y, Zhang Q, Peng S, Shen C, Yu Y, Zhang M, Yang W, Wu Q, Zhang Y, et al. 2017. Content decline of SERCA inhibitors saikosaponin A and D attenuates cardiotoxicity and hepatotoxicity of vinegar-baked Radix bupleuri. Environ Toxicol Pharmacol. 52:129–137.
  • Wong VK, Li T, Law BY, Ma ED, Yip NC, Michelangeli F, Law CK, Zhang MM, Lam KY, Chan PL, et al. 2013. Saikosaponin-D, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells. Cell Death Dis. 4:e720.
  • Wong VK, Zhang MM, Zhou H, Lam KY, Chan PL, Law CK, Yue PY, Liu L2. 2013. Saikosaponin-D enhances the anticancer potency of TNF-α via overcoming its undesirable response of activating NF-Kappa B signalling in cancer cells. Evid Based Complement Alternat Med. 2013:745295.
  • Wu S, Chen W, Liu K, Ren F, Zheng D, Xu F, Wu H. 2020. Saikosaponin D inhibits proliferation and induces apoptosis of non-small cell lung cancer cells by inhibiting the STAT3 pathway. J Int Med Res. 48(9):300060520937163.
  • Xiao K, Li K, Long S, Kong C, Zhu S. 2020. Potential molecular mechanisms of Chaihu-Shugan-San in treatment of breast cancer based on network pharmacology. Evid Based Complement Alternat Med. 2020:3670309.
  • Xu L, Ji Z, Guo L, Zhang R, Qu R, Ma S. 2018. Saikosaponin-D-mediated downregulation of neurogenesis results in cognitive dysfunction by inhibiting Akt/Foxg-1 pathway in mice. Toxicol Lett. 284:79–85.
  • Xu L, Song R, Tian JX, Tian Y, Liu GQ, Zhang ZJ. 2012. Analysis of saikosaponins in rat plasma by anionic adducts-based liquid chromatography tandem mass spectrometry method. Biomed Chromatogr. 26(7):808–815.
  • Yao M, Yang J, Cao L, Zhang L, Qu S, Gao H. 2014. Saikosaponin-D inhibits proliferation of DU145 human prostate cancer cells by inducing apoptosis and arresting the cell cycle at G0/G1 phase. Mol Med Rep. 10(1):365–372.
  • Yokota T, Wang Y. 2016. p38 MAP kinases in the heart. Gene. 575(2 Pt 2):369–376.
  • Yu P, Qiu H, Wang M, Tian Y, Zhang Z, Song R. 2017. In vitro metabolism study of saikosaponin D and its derivatives in rat liver microsomes. Xenobiotica. 47(1):11–19.
  • Yuan B, Yang R, Ma Y, Zhou S, Zhang X, Liu Y. 2017. A systematic review of the active saikosaponins and extracts isolated from Radix Bupleuri and their applications. Pharm Biol. 55(1):620–635.
  • Zhang CY, Jiang ZM, Ma XF, Li Y, Liu XZ, Li LL, Wu WH, Wang T. 2019. Saikosaponin-D inhibits the hepatoma cells and enhances chemosensitivity through SENP5-dependent inhibition of Gli1 SUMOylation under hypoxia. Front Pharmacol. 10:1039.
  • Zhang F, Chen L, Jin H, Shao J, Wu L, Lu Y, Zheng S. 2016. Activation of Fas death receptor pathway and Bid in hepatocytes is involved in saikosaponin D induction of hepatotoxicity. Environ Toxicol Pharmacol. 41:8–13.
  • Zhang G, Jin B, Li YP. 2011. C/EBPβ mediates tumour-induced ubiquitin ligase atrogin1/MAFbx upregulation and muscle wasting. Embo J. 30(20):4323–4335.
  • Zhao L, Li J, Sun ZB, Sun C, Yu ZH, Guo X. 2019. Saikosaponin D inhibits proliferation of human osteosarcoma cells via the p53 signaling pathway. Exp Ther Med. 17(1):488–494.
  • Zheng J, Chen J, Zou X, Zhao F, Guo M, Wang H, Zhang T, Zhang C, Feng W, Pessah IN, et al. 2019. Saikosaponin D causes apoptotic death of cultured neocortical neurons by increasing membrane permeability and elevating intracellular Ca2+ concentration. Neurotoxicology. 70:112–121.
  • Zhong D, Zhang HJ, Jiang YD, Wu P, Qi H, Cai C, Zheng SB, Dang Q. 2016. Saikosaponin-D: A potential chemotherapeutics in castration resistant prostate cancer by suppressing cancer metastases and cancer stem cell phenotypes. Biochem Biophys Res Commun. 474(4):722–729.
  • Zhu Y, Shi C, Zeng L, Liu G, Jiang W, Zhang X, Chen S, Guo J, Jian X, Ouyang J, et al. 2020. High COX-2 expression in cancer-associated fibiroblasts contributes to poor survival and promotes migration and invasiveness in nasopharyngeal carcinoma. Mol Carcinog. 59(3):265–280.