Cancer chemotherapy with novel bioactive natural products

doi:10.5246/jcps.2022.08.050

摘要/Abstract

摘要：

Cancer is the primary cause of death on a global scale. Every year, 8.8 million people die because lung, prostate gland, colorectal, and hepatic cancers are more common in men. In contrast, mammary glands, large intestine, bronchi, cervix, and abdomen cancers are more common in women. The Food and Drug Administration of the United States of America has approved plant-based medications for cancer treatment. Examples include taxanes, such as paclitaxel, and vinca alkaloids, such as vincristine and vinblastine. Although, developing new anti-cancer medicine to treat this disease will necessitate a diverse range of bioactive sources. More than 30 natural compounds derived from plants have been identified, with clinical trials currently underway. According to a literature review of numerous publications and manuals, novel medicinal compounds derived from bioactive sources have been confirmed scientifically efficacious against many kinds of cancer cells. The current study focused on new therapeutic compounds extracted from the plants indicated to have antineoplastic effects in clinical trials. The most significant discoveries of these active new medicinal substances were also summarized and discussed.

关键词: Alkaloids, Glycosides, Antitumar, Anticancer, Terpenoids

Abstract:

Key words: Alkaloids, Glycosides, Antitumar, Anticancer, Terpenoids

Supporting:

Neha Dangi, Shikha Sharma. Cancer chemotherapy with novel bioactive natural products[J]. 中国药学(英文版), 2022, 31(8): 589-607.

Neha Dangi, Shikha Sharma. Cancer chemotherapy with novel bioactive natural products[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(8): 589-607.

图/表 31

Figure 1. The structure of vinblastine.

Figure 2. The structures of naucleaoral A and B.

Figure 3. The structure of schiskiniin.

Figure 4. The structure of arctigenin.

Figure 5. The structure of berberine.

Figure 6. The structure of sanguinarine.

Figure 7. The structure of clivorine.

Figure 8. The structure of antofine.

Figure 9. The structures of tylophorine, tylophoridine, and pergularine.

Figure 10. The structures of hypoestestatin 1 and 2.

Figure 11. The structure of oxymatrine.

Figure 12. The structure of prisconnatanone A.

Figure 13. The structure of hypericin.

Figure 14. The structure of digoxin.

Figure 15. The structure of linamarin.

Figure 16. The structure of amygdalin.

Figure 17. The structure of andrographolide.

Figure 18. The structure of excisanin A.

Figure 19. The structure of oridonin.

Figure 20. The structures of ardisiacrispins A and B.

Figure 21. The structure of astragaloside IV.

Figure 22. The structure of AS.

Figure 23. The structure of butelinic acid.

Figure 24. The strucuture of cucurbitacin B.

Figure 25. The structure of EA.

Figure 26. The structure of Ganoderiol F.

Figure 27. The structure of lucidenic acid L.

Figure 28. The structure of lupeol.

Figure 29. The structure of waltonitone.

Figure 30. The structure of lycopene.

Figure 31. The structure of zerumbone.

参考文献 101

[1]	Mangal, M.; Sagar, P.; Singh, H.; Raghava, G.P.S.; Agarwal, S.M. NPACT: naturally occurring plant-based anti-cancer compound-activity-target database. Nucleic Acids Res. 2012, 41, D1124–D1129.
[2]	Balunas, M.J.; Kinghorn, A.D. Drug discovery from medicinal plants. Life Sci. 2005, 78, 431–441.
[3]	Kinghorn, A.D. Drug discovery from natural products. In: Foye’s Principles of Medicinal Chemistry, 6th ed.; Lemke, T.L.; Williams, D.A.; Eds.; Philadelphia, PA, USA: Wolters Kluwer/Williams & Wilkins. 2008, 12–25.
[4]	Howes, M.J.R. The evolution of anticancer drug discovery from plants. Lancet Oncol. 2018, 19, 293–294.
[5]	Cragg, G.M.; Grothaus, P.G.; Newman, D.J. Impact of natural products on developing new anti-cancer agents. Chem. Rev. 2009, 109, 3012–3043.
[6]	Jordan, M.A.; Thrower, D.; Wilson, L. Mechanism of inhibition of cell proliferation by Vinca alkaloids. Cancer Res. 1991, 51, 2212–2222.
[7]	Cragg, G.M.; Newman, D.J. Plants as a source of anti-cancer agents. J. Ethnopharmacol. 2005, 100, 72–79.
[8]	Craig, S.L.; Jensen, V.B. Animal models in cancer nanotechnology. Nanotechnology in Cancer. 2017, 45–69.
[9]	Sichaem, J.; Surapinit, S.; Siripong, P.; Khumkratok, S.; Jong-aramruang, J.; Tip-pyang, S. Two new cytotoxic isomeric indole alkaloids from the roots of Nauclea orientalis. Fitoterapia. 2010, 81, 830–833.
[10]	Shoeb, M.; Celik, S.; Jaspars, M.; Kumarasamy, Y.; MacManus, S.M.; Nahar, L.; Thoo-Lin, P.K.; Sarker, S.D. Isolation, structure elucidation and bioactivity of schischkiniin, a unique indole alkaloid from the seeds of Centaurea schischkinii. Tetrahedron. 2005, 61, 9001–9006.
[11]	Zhang, M.D.; Cai, S.Z.; Zuo, B.; Gong, W.; Tang, Z.H.; Zhou, D.; Weng, M.Z.; Qin, Y.Y.; Wang, S.H.; Liu, J.; Ma, F.; Quan, Z.W. Arctigenin induced gallbladder cancer senescence through modulating epidermal growth factor receptor pathway. Tumour Biol. 2017, 39, 1010428317698359.
[12]	Zhou, J.; Feng, J.H.; Fang, L. A novel monoterpenoid indole alkaloid with anticancer activity from Melodinus khasianus. Bioorg. Med. Chem. Lett. 2017, 27, 893–896.
[13]	Low, Y.Y.; Lim, K.H.; Choo, Y.M.; Pang, H.S.; Etoh, T.; Hayashi, M.; Komiyama, K.; Kam, T.S. Structure, biological activity, and a biomimetic partial synthesis of the lirofolines, novel pentacylic indole alkaloids from Tabernaemontana. Tetrahedron Lett. 2010, 51, 269–272.
[14]	de Sá Alves, F.R.; Barreiro, E.J.; Fraga, C.A.M. From nature to drug discovery: the indole scaffold as a ‘privileged structure’. Mini Rev. Med. Chem. 2009, 9, 782–793.
[15]	Cardoso, D.S.P.; Kincses, A.; Nové, M.; Spengler, G.; Mulhovo, S.; Aires-de-Sousa, J.; dos Santos, D.J.V.A.; Ferreira, M.J.U. Alkylated monoterpene indole alkaloid derivatives as potent P-glycoprotein inhibitors in resistant cancer cells. Eur. J. Med. Chem. 2021, 210, 112985.
[16]	Fukuda, K.; Hibiya, Y.; Mutoh, M.; Koshiji, M.; Akao, S.; Fujiwara, H. Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells. J. Ethnopharmacol. 1999, 66, 227–233.
[17]	Letašiová, S.; Jantová, S.; Miko, M.; Ovádeková, R.; Horváthová, M. Effect of berberine on proliferation, biosynthesis of macromolecules, cell cycle and induction of intercalation with DNA, dsDNA damage and apoptosis in Ehrlich ascites carcinoma cells. J. Pharm. Pharmacol. 2010, 58, 263–270.
[18]	Wang, N.; Feng, Y.B.; Zhu, M.F.; Tsang, C.M.; Man, K.; Tong, Y.; Tsao, S.W. Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: the cellular mechanism. J. Cell Biochem. 2010, 111, 1426–1436.
[19]	Chen, X.M.; Zhang, M.; Fan, P.L.; Qin, Y.H.; Zhao, H.W. Chelerythrine chloride induces apoptosis in renal cancer HEK-293 and SW-839 cell lines. Oncol. Lett. 2016, 11, 3917–3924.
[20]	Jang, B.C.; Park, J.G.; Song, D.K.; Baek, W.K.; Yoo, S.K.; Jung, K.H.; Park, G.Y.; Lee, T.Y.; Suh, S.I. Sanguinarine induces apoptosis in A549 human lung cancer cells primarily via cellular glutathione depletion. Toxicol. Vitro. 2009, 23, 281–287.
[21]	de Stefano, I.; Raspaglio, G.; Zannoni, G.F.; Travaglia, D.; Prisco, M.G.; Mosca, M.; Ferlini, C.; Scambia, G.; Gallo, D. Antiproliferative and antiangiogenic effects of the benzophenanthridine alkaloid sanguinarine in melanoma. Biochem. Pharmacol. 2009, 78, 1374–1381.
[22]	Pallichankandy, S.; Rahman, A.; Thayyullathil, F.; Galadari, S. ROS-dependent activation of autophagy is a critical mechanism for the induction of anti-glioma effect of sanguinarine. Free. Radic. Biol. Med. 2015, 89, 708–720.
[23]	Chang, H.C.; Chang, F.R.; Wu, Y.C.; Lai, Y.H. Anti-cancer effect of liriodenine on human lung cancer cells. Kaohsiung J. Med. Sci. 2004, 20, 365–371.
[24]	Nordin, N.; Majid, N.A.; Hashim, N.M.; Rahman, M.A.; Hassan, Z.; Ali, H.M. Liriodenine, an aporphine alkaloid from Enicosanthellum pulchrum, inhibits proliferation of human ovarian cancer cells through induction of apoptosis via the mitochondrial signaling pathway and blocking cell cycle progression. Drug Des. Dev. Ther. 2015, 9, 1437–1448.
[25]	Tuzimski, T.; Petruczynik, A.; Kaproń, B.; Makuch-Kocka, A.; Szultka-Młyńska, M.; Misiurek, J.; Szymczak, G.; Buszewski, B. Determination of cytotoxic activity of selected isoquinoline alkaloids and plant extracts obtained from various parts of mahonia aquifolium collected in various vegetation seasons. Molecules. 2021, 26, 816.
[26]	Xu, L.; Yang, W.; Hu, J.; Han, C.M.; Li, P.F. Three new isoquinoline alkaloids from the whole plants of Thalictrum tenue with cytotoxic activities. J. Asian Nat. Prod. Res. 2020, 22, 618–625.
[27]	Bandyopadhyay, D.; Mukherjee, S.; Granados, J.C.; Short, J.D.; Banik, B.K. Ultrasound-assisted bismuth nitrate-induced green synthesis of novel pyrrole derivatives and their biological evaluation as anticancer agents. Eur. J. Med. Chem. 2012, 50, 209–215.
[28]	Ji, L.L.; Zhang, M.; Sheng, Y.C.; Wang, Z.T. Pyrrolizidine alkaloid clivorine induces apoptosis in human normal liver L-02 cells and reduces the expression of p53 protein. Toxicol. Vitro. 2005, 19, 41–46.
[29]	Liu, W.J.; Li, X.; Zhou, B.; Fang, S.C.; Ho, W.; Chen, H.; Liang, H.; Ye, L.; Tang, J. Differential induction of apoptosis and autophagy by pyrrolizidine alkaloid clivorine in human hepatoma Huh-7.5 cells and its toxic implication. PLoS One. 2017, 12, e0179379.
[30]	Bai, N.S.; He, K.; Roller, M.; Lai, C.S.; Bai, L.; Pan, M.H. Flavonolignans and other constituents from Lepidium meyenii with activities in anti-inflammation and human cancer cell lines. J. Agric. Food Chem. 2015, 63, 2458–2463.
[31]	Zhou, M.; Zhou, K.; Gao, X.M.; Jiang, Z.Y.; Lv, J.J.; Liu, Z.H.; Yang, G.Y.; Miao, M.M.; Che, C.T.; Hu, Q.F. Fistulains A and B, new bischromones from the bark of cassia fistula, and their activities. Org. Lett. 2015, 17, 2638–2641.
[32]	Zhou, M.; Ma, H.Y.; Liu, Z.H.; Yang, G.Y.; Du, G.; Ye, Y.Q.; Li, G.P.; Hu, Q.F. (+)-meyeniins A–C, novel hexahydroimidazo[1,5-c]thiazole derivatives from the tubers of Lepidium meyenii: complete structural elucidation by biomimetic synthesis and racemic crystallization. J. Agric. Food Chem. 2017, 65, 1887–1892.
[33]	Zhou, M.; Zhang, R.Q.; Chen, Y.J.; Liao, L.M.; Sun, Y.Q.; Ma, Z.H.; Yang, Q.F.; Li, P.; Ye, Y.Q.; Hu, Q.F. Three new pyrrole alkaloids from the roots of Lepidium meyenii. Phytochem. Lett. 2018, 23, 137–140.
[34]	Mandhare, A.; Dhulap, S.A.; Dhulap, A.S. Review on the Anticancer and in-silico binding studies of Phenanthroindolizidine alkaloids. Chem. Inform. 2015, 1, 1–15.
[35]	Cordell, G.A.; Suffness, M. Antitumor Alkaloids In: The Alkaloids: Chemistry and Pharmacology. A.R. Brossi, Ed.; Academic Press, Inc, Harcourt Brace Jovanovich Publisher, Orlando, Florida, USA. 1985, 25, 1–357.
[36]	Wu, C.M.; Yang, C.W.; Lee, Y.Z.; Chuang, T.H.; Wu, P.L.; Chao, Y.S.; Lee, S.J. Tylophorine arrests carcinoma cells at G1 phase by downregulating cyclin A2 expression. Biochem. Biophys. Res. Commun. 2009, 386, 140–145.
[37]	Rao, K.N.; Venkatachalam, S.R. Inhibition of dihydrofolate reductase and cell growth activity by the phenanthroindolizidine alkaloids pergularinine and tylophorinidine: the in vitro cytotoxicity of these plant alkaloids and their potential as antimicrobial and anticancer agents. Toxicol. Vitro. 2000, 14, 53–59.
[38]	Pettit, G.R.; Goswami, A.; Cragg, G.M.; Schmidt, J.M.; Zou, J.C. Antineoplastic agents, 103. the isolation and structure of hypoestestatins 1 and 2 from the east African hypoëstes verticillaris. J. Nat. Prod. 1984, 47, 913–919.
[39]	Yap, V.A.; Loong, B.J.; Ting, K.N.; Loh, S.H.S.; Yong, K.T.; Low, Y.Y.; Kam, T.S.; Lim, K.H. Hispidacine, an unusual 8,4'-oxyneolignan-alkaloid with vasorelaxant activity, and hispiloscine, an antiproliferative phenanthroindolizidine alkaloid, from ficus hispida Linn. Phytochemistry. 2015, 109, 96–102.
[40]	Nafisi, S.; Bonsaii, M.; Maali, P.; Khalilzadeh, M.A.; Manouchehri, F. Β-carboline alkaloids bind DNA. J. Photochem. Photobiol. B Biol. 2010, 100, 84–91.
[41]	Narasimha Rao, K.; Bhattacharya, R.K.; Venkatachalam, S.R. β-Carboline-benzoquinolizidine alkaloid deoxytubulosine inhibits thymidylate synthase activity in leukemic leukocytes from patients with chronic myeloblastic leukemia and acute lymphoblastic leukemia. Anti Cancer Drugs. 1998, 9, 727–732.
[42]	Liu, Y.; Xu, Y.; Ji, W.D.; Li, X.Y.; Sun, B.; Gao, Q.G.; Su, C.Q. Anti-tumor activities of matrine and oxymatrine: literature review. Tumour Biol. 2014, 35, 5111–5119.
[43]	Wang, K.B.; Li, D.H.; Hu, P.; Wang, W.J.; Lin, C.; Wang, J.; Lin, B.; Bai, J.; Pei, Y.H.; Jing, Y.K.; Li, Z.L.; Yang, D.Z.; Hua, H.M. A series of β-carboline alkaloids from the seeds of peganum harmala show G-quadruplex interactions. Org. Lett. 2016, 18, 3398–3401.
[44]	Wang, X.D.; Li, C.Y.; Jiang, M.M.; Li, D.; Wen, P.; Song, X.; Chen, J.D.; Guo, L.X.; Hu, X.P.; Li, G.Q.; Zhang, J.; Wang, C.H.; He, Z.D. Induction of apoptosis in human leukemia cells through an intrinsic pathway by cathachunine, a unique alkaloid isolated from Catharanthus roseus. Phytomedicine. 2016, 23, 641–653.
[45]	Liu, M.H.; Jing, X.B.; Cai, X.B.; Chen, S.Z.; Cai, J.Y. The mechanism about the inhibition effects of emodin on the proliferation of EC-109 cell in esophageal cancer. J. Shantou Univ. Med. Coll. 2009, 22, 12–14, 67.
[46]	Trybus, W.; Król, G.; Trybus, E.; Stachurska, A.; Kopacz- Bednarska, A.; Król, T. Aloe-emodin influence on the lysosomal compartment of hela cells. Asian Pac. J. Cancer Prev. 2017, 18, 3273–3279.
[47]	Li, B.; Zhang, D.M.; Luo, Y.M.; Chen, X.G. Three new and antitumor anthraquinone glycosides from lasianthus acuminatissimus MERR. Chem. Pharm. Bull. 2006, 54, 297–300.
[48]	Lu, C.C.; Yang, J.S.; Huang, A.C.; Hsia, T.C.; Chou, S.T.; Kuo, C.L.; Lu, H.F.; Lee, T.H.; Wood, W.G.; Chung, J.G. Chrysophanol induces necrosis through the production of ROS and alteration of ATP levels in J5 human liver cancer cells. Mol. Nutr. Food Res. 2010, 54, 967–976.
[49]	Li, N.; Cui, R.J.; Zhao, X.S.; Liang, J.Y. 2-Methyl-3-hydroxy-anthraquinone induces Ca²⁺-mediated apoptosis in human MCF-7 breast cancer cells. J. China Pharm. Univ. 2011, 42, 365–368.
[50]	Wan, X.X.; Zhang, H.; Wang, J.H. 2-Hydroxy-3-methylanthraquinone from Hedyotis diffusa Willd induces the apoptosis of HO-8910 cells through Fas/FasL signaling pathway. Pract. Pharm. Clin. Remedies. 2015, 18, 1405–1409.
[51]	Feng, S.X.; Zhang, M.; Xu, J.; Hu, Y.M. Prisconnatanones A, a cytotoxic naphthoquinone from Prismatomeris connata, suppresses the proliferation of human laryngocarcinoma HEp-2 cells in vitro. Nat. Prod. Res. 2016, 30, 2840–2844.
[52]	Sun, Y.X.; Meng, Y.; Dong, Z.; Yang, Z.Q. Effects of hypericin associated with light irradiation on human laryngeal squamous cell carcinoma strain Hep-2. Chin. J. Otorhinolaryngol. Head Neck Surg. 2005, 40, 128–132.
[53]	Clifford, R.J.; Kaplan, J.H. Human breast tumor cells are more resistant to cardiac glycoside toxicity than non-tumorigenic breast cells. PLoS One. 2013, 8, e84306.
[54]	Stenkvist, B.; Bengtsson, E.; Eriksson, O.; Holmquist, J.; Nordin, B.; Westman-Naeser, S.; Eklund, G. Cardiac glycosides and breast cancer. Lancet. 1979, 313, 563.
[55]	Wang, Y.; Lonard, D.M.; Yu, Y.; Chow, D.C.; Palzkill, T.G.; Wang, J.; Qi, R.G.; Matzuk, A.J.; Song, X.Z.; Madoux, F.; Hodder, P.; Chase, P.; Griffin, P.R.; Zhou, S.L.; Liao, L.; Xu, J.M.; O'Malley, B.W. Bufalin is a potent small-molecule inhibitor of the steroid receptor coactivators SRC-3 and SRC-1. Cancer Res. 2014, 74, 1506–1517.
[56]	Zhang, D.M.; Liu, J.S.; Tang, M.K.; Yiu, A.; Cao, H.H.; Jiang, L.; Yuet-Wa Chan, J.; Tian, H.Y.; Fung, K.P.; Ye, W.C. Bufotalin from Venenum Bufonis inhibits growth of multidrug resistant HepG2 cells through G2/M cell cycle arrest and apoptosis. Eur. J. Pharmacol. 2012, 692, 19–28.
[57]	Zhang, D.M.; Liu, J.S.; Deng, L.J.; Chen, M.F.; Yiu, A.; Cao, H.H.; Tian, H.Y.; Fung, K.P.; Kurihara, H.; Pan, J.X.; Ye, W.C. Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway. Carcinogenesis. 2013, 34, 1331–1342.
[58]	Beheshti Zavareh, R.; Lau, K.S.; Hurren, R.; Datti, A.; Ashline, D.J.; Gronda, M.; Cheung, P.; Simpson, C.D.; Liu, W.; Wasylishen, A.R.; Boutros, P.C.; Shi, H.; Vengopal, A.; Jurisica, I.; Penn, L.Z.; Reinhold, V.N.; Ezzat, S.; Wrana, J.; Rose, D.R.; Schachter, H.; Dennis, J.W.; Schimmer, A.D. Inhibition of the sodium/potassium ATPase impairs N-glycan expression and function. Cancer Res. 2008, 68, 6688–6697.
[59]	Badr, C.E.; Wurdinger, T.; Nilsson, J.; Niers, J.M.; Whalen, M.; Degterev, A.; Tannous, B.A. Lanatoside C sensitizes glioblastoma cells to tumor necrosis factor-related apoptosis-inducing ligand and induces an alternative cell death pathway. Neuro Oncol. 2011, 13, 1213–1224.
[60]	White, Arias-Garzon, McMahon, Sayre. Cyanogenesis in cassava. The role of hydroxynitrile lyase in root cyanide production. Plant Physiol. 1998, 116, 1219–1225.
[61]	Kato, Y.; Terada, H. Determination method of linamarin in cassava products and beans by ultra high performance liquid chromatography with tandem mass spectrometry. Food Hyg. Saf. Sci. Shokuhin Eiseigaku Zasshi. 2014, 55, 162–166.
[62]	Mosayyebi, B.; Imani, M.; Mohammadi, L.; Akbarzadeh, A.; Zarghami, N.; Edalati, M.; Alizadeh, E.; Rahmati, M. An update on the toxicity of cyanogenic glycosides bioactive compounds: possible clinical application in targeted cancer therapy. Mater. Chem. Phys. 2020, 246, 122841.
[63]	Idibie, C.A.; Davids, H.; Iyuke, S.E. Cytotoxicity of purified cassava linamarin to a selected cancer cell lines. Bioprocess Biosyst. Eng. 2007, 30, 261–269.
[64]	Yusuf, U.F.; Ahmadun, F.R.; Rosli, R.; Iyuke, S.E.; Billa, N.; Abdullah, N.; Umar-Tsafe, N. An in vitro inhibition of human malignant cell growth of crude water extract of cassava (Manihot esculenta Crantz) and commercial linamarin. Songklanakarin J. Sci. Technol. 2006, 28, 145.
[65]	García-Escudero, V.; Gargini, R. Autophagy induction as an efficient strategy to eradicate tumors. Autophagy. 2008, 4, 923–925.
[66]	Sireesha, D.; Siva Reddy, B.; Reginald, B.; Samatha, M.; Kamal, F. Effect of amygdalin on oral cancer cell line: an in vitro study. J. Oral Maxillofac. Pathol. 2019, 23, 104–107.
[67]	Chang, H.K.; Shin, M.S.; Yang, H.Y.; Lee, J.W.; Kim, Y.S.; Lee, M.H.; Kim, J.; Kim, K.H.; Kim, C.J. Amygdalin induces apoptosis through regulation of Ba_x and Bcl-2 expressions in human DU145 and LNCaP prostate cancer cells. Biol. Pharm. Bull. 2006, 29, 1597–1602.
[68]	Blaheta, R.A.; Nelson, K.; Haferkamp, A.; Juengel, E. Amygdalin, quackery or cure? Phytomedicine. 2016, 23, 367–376.
[69]	Moertel, C.G.; Ames, M.M.; Kovach, J.S.; Moyer, T.P.; Rubin, J.R.; Tinker, J.H. A pharmacologic and toxicological study of amygdalin. JAMA. 1981, 245, 591–594.
[70]	Thoppil, R.J.; Bishayee, A. Terpenoids as potential chemopreventive and therapeutic agents in liver cancer. World J. Hepatol. 2011, 3, 228–249.
[71]	Rabi, T.; Bishayee, A. Terpenoids and breast cancer chemoprevention. Breast Cancer Res. Treat. 2009, 115, 223–239.
[72]	Galle, M.; Crespo, R.; Rodenak Kladniew, B.; Montero Villegas, S.; Polo, M.; de Bravo, M.G. Suppression by geraniol of the growth of A549 human lung adenocarcinoma cells and inhibition of the mevalonate pathway in culture and in vivo: potential use in cancer chemotherapy. Nutr. Cancer. 2014, 66, 888–895.
[73]	Carnesecchi, S.; Schneider, Y.; Ceraline, J.; Duranton, B.; Gosse, F.; Seiler, N.; Raul, F. Geraniol, a component of plant essential oils, inhibits growth and polyamine biosynthesis in human colon cancer cells. J. Pharmacol. Exp. Ther. 2001, 298, 197–200.
[74]	Kim, S.H.; Bae, H.C.; Park, E.J.; Lee, C.R.; Kim, B.J.; Lee, S.; Park, H.H.; Kim, S.J.; So, I.; Kim, T.W.; Jeon, J.H. Geraniol inhibits prostate cancer growth by targeting cell cycle and apoptosis pathways. Biochem. Biophys. Res. Commun. 2011, 407, 129–134.
[75]	Burke, Y.D.; Stark, M.J.; Roach, S.L.; Sen, S.E.; Crowell, P.L. Inhibition of pancreatic cancer growth by the dietary isoprenoids farnesol and geraniol. Lipids. 1997, 32, 151.
[76]	Ong, T.P.; Heidor, R.; de Conti, A.; Dagli, M.L.Z.; Moreno, F.S. Farnesol and geraniol chemopreventive activities during the initial phases of hepatocarcinogenesis involve similar actions on cell proliferation and DNA damage, but distinct actions on apoptosis, plasma cholesterol and HMGCoA reductase. Carcinogenesis. 2005, 27, 1194–1203.
[77]	Yang, W.Q.; Chen, X.; Li, Y.L.; Guo, S.F.; Wang, Z.; Yu, X.L. Advances in pharmacological activities of terpenoids. Nat. Prod. Commun. 2020, 15, 1–13.
[78]	Polo, M.P.; de Bravo, M.G. Effect of geraniol on fatty-acid and mevalonate metabolism in the human hepatoma cell line Hep G2. Biochem. Cell Biol. 2006, 84, 102–111.
[79]	Ji, L.L.; Liu, T.Y.; Liu, J.; Chen, Y.; Wang, Z.T. Andrographolide inhibits human hepatoma-derived Hep3B cell growth through the activation of c-Jun N-terminal kinase. Planta Med. 2007, 73, 1397–1401.
[80]	Deng, R.; Tang, J.; Xia, L.P.; Li, D.D.; Zhou, W.J.; Wang, L.L.; Feng, G.K.; Zeng, Y.X.; Gao, Y.H.; Zhu, X.F. ExcisaninA, a diterpenoid compound purified from Isodon MacrocalyxinD, induces tumor cells apoptosis and suppresses tumor growth through inhibition of PKB/AKT kinase activity and blockade of its signal pathway. Mol. Cancer Ther. 2009, 8, 873–882.
[81]	Huang, J.; Wu, L.J.; Tashiro, S.I.; Onodera, S.; Ikejima, T. Reactive oxygen species mediate oridonin-induced HepG2 apoptosis through p53, MAPK, and mitochondrial signaling pathways. J. Pharmacol. Sci. 2008, 107, 370–379.
[82]	Li, M.; Wei, S.Y.; Xu, B.; Guo, W.; Liu, D.L.; Cui, J.R.; Yao, X.S. Pro-apoptotic and microtubule-disassembly effects of ardisiacrispin (A+B), triterpenoid saponins from Ardisia crenata on human hepatoma Bel-7402 cells. J. Asian Nat. Prod. Res. 2008, 10, 729–736.
[83]	Qi, H.Y.; Wei, L.; Han, Y.F.; Zhang, Q.L.; Lau, A.S.Y.; Rong, J.H. Proteomic characterization of the cellular response to chemopreventive triterpenoid astragaloside IV in human hepatocellular carcinoma cell line HepG2. Int. J. Oncol. 2010, 36, 725–735.
[84]	Lee, Y.S.; Jin, D.Q.; Kwon, E.J.; Park, S.H.; Lee, E.S.; Jeong, T.C.; Nam, D.H.; Huh, K.; Kim, J.A. Asiatic acid, a triterpene, induces apoptosis through intracellular Ca²⁺ release and enhanced expression of p53 in HepG2 human hepatoma cells. Cancer Lett. 2002, 186, 83–91.
[85]	Eichenmüller, M.; von Schweinitz, D.; Kappler, R. Betulinic acid treatment promotes apoptosis in hepatoblastoma cells. Int. J. Oncol. 2009, 35, 873–879.
[86]	Chan, K.T.; Meng, F.Y.; Li, Q.; Ho, C.Y.; Lam, T.S.; To, Y.; Lee, W.H.; Li, M.; Chu, K.H.; Toh, M. Cucurbitacin B induces apoptosis and S phase cell cycle arrest in BEL-7402 human hepatocellular carcinoma cells and is effective via oral administration. Cancer Lett. 2010, 294, 118–124.
[87]	Takahashi, N.; Yoshida, Y.; Sugiura, T.; Matsuno, K.; Fujino, A.; Yamashita, U. Cucurbitacin D isolated from Trichosanthes kirilowii induces apoptosis in human hepatocellular carcinoma cells in vitro. Int. Immunopharmacol. 2009, 9, 508–513.
[88]	Tong, X.H.; Lin, S.G.; Fujii, M.; Hou, D.X. Molecular mechanisms of echinocystic acid-induced apoptosis in HepG2 cells. Biochem. Biophys. Res. Commun. 2004, 321, 539–546.
[89]	Chang, U.M.; Li, C.H.; Lin, L.I.; Huang, C.P.; Kan, L.S.; Lin, S.B. Ganoderiol F, a ganoderma triterpene, induces senescence in hepatoma HepG2 cells. Life Sci. 2006, 79, 1129–1139.
[90]	Weng, C.J.; Chau, C.F.; Chen, K.D.; Chen, D.H.; Yen, G.C. The anti-invasive effect of lucidenic acids isolated from a new Ganoderma lucidum strain. Mol. Nutr. Food Res. 2007, 51, 1472–1477.
[91]	Zhang, L.; Zhang, Y.C.; Zhang, L.Y.; Yang, X.J.; Lv, Z.C. Lupeol, a dietary triterpene, inhibited growth, and induced apoptosis through down-regulation of DR3 in SMMC7721 cells. Cancer Investig. 2009, 27, 163–170.
[92]	Yan, S.L.; Huang, C.Y.; Wu, S.T.; Yin, M.C. Oleanolic acid and ursolic acid induce apoptosis in four human liver cancer cell lines. Toxicol. Vitro. 2010, 24, 842–848.
[93]	Tian, Z.; Lin, G.; Zheng, R.X.; Huang, F.; Yang, M.S.; Xiao, P.G. Anti-hepatoma activity and mechanism of ursolic acid and its derivatives isolated from Aralia decaisneana. World J. Gastroenterol. 2006, 12, 874–879.
[94]	Zhang, Z.; Wang, S.; Qiu, H.; Duan, C.H.; Ding, K.; Wang, Z.T. Waltonitone induces human hepatocellular carcinoma cells apoptosis in vitro and in vivo. Cancer Lett. 2009, 286, 223–231.
[95]	Huang, C.S.; Shih, M.K.; Chuang, C.H.; Hu, M.L. Lycopene inhibits cell migration and invasion and upregulates Nm23-H1 in a highly invasive hepatocarcinoma, SK-hep-1 cells. J. Nutr. 2005, 135, 2119–2123.
[96]	Kozuki, Y.; Miura, Y.; Yagasaki, K. Inhibitory effects of carotenoids on the invasion of rat ascites hepatoma cells in culture. Cancer Lett. 2000, 151, 111–115.
[97]	Das, S.K.; Hashimoto, T.; Kanazawa, K. Growth inhibition of human hepatic carcinoma HepG2 cells by fucoxanthin is associated with down-regulation of cyclin D. Biochim. Biophys. Acta BBA Gen. Subj. 2008, 1780, 743–749.
[98]	Chen, W.; Hou, J.; Yin, Y.; Jang, J.; Zheng, Z.L.; Fan, H.D.; Zou, G.L. Alpha-Bisabolol induces dose- and time-dependent apoptosis in HepG2 cells via a Fas- and mitochondrial-related pathway, involves p53 and NFkappaB. Biochem. Pharmacol. 2010, 80, 247–254.
[99]	Hsu, Y.L.; Wu, L.Y.; Kuo, P.L. Dehydrocostuslactone, a medicinal plant-derived sesquiterpene lactone, induces apoptosis coupled to endoplasmic reticulum stress in liver cancer cells. J. Pharmacol. Exp. Ther. 2009, 329, 808–819.
[100]	Yu, X.; Yang, F.Q.; Li, S.P.; Gao, J.L.; Hu, G.; Sin-Cheng, L.; Emilia, C.L.; Kwok-Pui, F.; Wang, Y.T.; Simon, L.M.Y. Furanodiene induces G2/M cell cycle arrest and apoptosis through MAPK signaling and mitochondria-caspase pathway in human hepatocellular carcinoma cells. Cancer Biol. Ther. 2007, 6, 1044–1050.
[101]	Sakinah, S.A.S.; Handayani, S.T.; Hawariah, L.P.A. Zerumbone induced apoptosis in liver cancer cells via modulation of Bax/Bcl-2 ratio. Cancer Cell Int. 2007, 7, 4.