Betulinic Acid and Brosimine B Hybrid Derivatives as Potential Agents against Female Cancers

Author(s): Nádia M. Garcês de Couto, Júlia B. Willig, Thaís C. Ruaro, Diogo Losch de Oliveira, Andréia Buffon, Diogo A. Pilger, Mara S.P. Arruda, Diogo Miron, Aline R. Zimmer, Simone C.B. Gnoatto*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 5 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Cancer is a multifactorial disease, representing one of the leading causes of death worldwide. On a global estimate, breast cancer is the most frequently occurring cancer in women and cervical cancer, the fourth most common. Both types of cancer remain the major cause of cancer-related mortality in developing countries. A strategy for rational drug design is hybridization, which aims to bring together in one molecule, two or more pharmacophores in order to reach several biological targets.

Objective: The objective of this work was to develop new hybrids based on natural pharmacophores: Betulinic acid (1) and brosimine b (2), active in female cancer cell lines.

Methods: The coupling reactions were carried out by Steglich esterification. Different compounds were designed for the complete and simplified structural hybridization of molecules. The anticancer activities of the compounds were evaluated in human cervical adenocarcinoma (HeLa), human cervical metastatic epidermoid carcinoma (ME-180), and human breast adenocarcinoma (MCF-7) cell lines.

Results: Hybrid 3 presented higher potency (IC50 = 9.2 ± 0.5μM) and SI (43.5) selectively in MCF-7 cells (in relation to Vero cells) with its cytotoxic effect occurring via apoptosis. In addition, compound 6 showed activity in MCF-7 and HeLa cells with intermediate potency, but with high efficacy, acting via apoptosis as well.

Conclusion: In this context, we showed that the combination of two complex structures generated the development of hybrids with differing inhibitory profiles and apoptotic modes of action, thus representing potential alternatives in female cancer treatment.

Keywords: Hybrid compounds, triterpene, betulinic acid, flavonoid, anticancer activity, female cancer.

[1]
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
[http://dx.doi.org/10.1002/ijc.29210] [PMID: 25220842]
[2]
Fitzmaurice, C.; Allen, C.; Barber, R.M.; Barregard, L.; Bhutta, Z.A.; Brenner, H.; Dicker, D.J.; Chimed-Orchir, O.; Dandona, R.; Dandona, L. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015. JAMA Oncol., 2017, 3(4), 524.
[http://dx.doi.org/10.1001/jamaoncol.2016.5688] [PMID: 27918777]
[3]
Torre, L.A.; Islami, F.; Siegel, R.L.; Ward, E.M.; Jemal, A. Global cancer in women: Burden and trends. Cancer Epidemiol. Biomarkers Prev., 2017, 26(4), 444-457.
[http://dx.doi.org/10.1158/1055-9965.EPI-16-0858] [PMID: 28223433]
[4]
Cragg, G.M.; Pezzuto, J.M. Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents. Med. Princ. Pract., 2016, 25(2)(Suppl. 2), 41-59.
[http://dx.doi.org/10.1159/000443404] [PMID: 26679767]
[5]
Guo, Z. The modification of natural products for medical use. Acta Pharm. Sin. B, 2017, 7(2), 119-136.
[http://dx.doi.org/10.1016/j.apsb.2016.06.003] [PMID: 28303218]
[6]
Yogeeswari, P.; Sriram, D. Betulinic acid and its derivatives: a review on their biological properties. Curr. Med. Chem., 2005, 12(6), 657-666.
[http://dx.doi.org/10.2174/0929867053202214] [PMID: 15790304]
[7]
Pai, S.R.; Joshi, R.K. Distribution of betulinic acid in plant kingdom. Plant Sci. Today, 2014, 1(3), 103-107.
[http://dx.doi.org/10.14719/pst.2014.1.3.58]
[8]
Fulda, S. Betulinic Acid for cancer treatment and prevention. Int. J. Mol. Sci., 2008, 9(6), 1096-1107.
[http://dx.doi.org/10.3390/ijms9061096] [PMID: 19325847]
[9]
Sawada, N.; Kataoka, K.; Kondo, K.; Arimochi, H.; Fujino, H.; Takahashi, Y.; Miyoshi, T.; Kuwahara, T.; Monden, Y.; Ohnishi, Y. Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice. Br. J. Cancer, 2004, 90(8), 1672-1678.
[http://dx.doi.org/10.1038/sj.bjc.6601746] [PMID: 15083202]
[10]
Xu, T.; Pang, Q.; Wang, Y.; Yan, X. Betulinic acid induces apoptosis by regulating PI3K/Akt signaling and mitochondrial pathways in human cervical cancer cells. Int. J. Mol. Med., 2017, 40(6), 1669-1678.
[http://dx.doi.org/10.3892/ijmm.2017.3163] [PMID: 29039440]
[11]
Luo, R.; Fang, D.; Chu, P.; Wu, H.; Zhang, Z.; Tang, Z. Multiple molecular targets in breast cancer therapy by betulinic acid. Biomed. Pharmacother., 2016, 84, 1321-1330.
[http://dx.doi.org/10.1016/j.biopha.2016.10.018] [PMID: 27810789]
[12]
Tiwari, R.; Puthli, A.; Balakrishnan, S.; Sapra, B.K.; Mishra, K.P. Betulinic acid-induced cytotoxicity in human breast tumor cell lines MCF-7 and T47D and its modification by tocopherol. Cancer Invest., 2014, 32(8), 402-408.
[http://dx.doi.org/10.3109/07357907.2014.933234] [PMID: 25019212]
[13]
Nakagawa-Goto, K.; Yamada, K.; Taniguchi, M.; Tokuda, H.; Lee, K.H. Cancer preventive agents 9. Betulinic acid derivatives as potent cancer chemopreventive agents. Bioorg. Med. Chem. Lett., 2009, 19(13), 3378-3381.
[http://dx.doi.org/10.1016/j.bmcl.2009.05.050] [PMID: 19481937]
[14]
Mullauer, F.B.; Kessler, J.H.; Medema, J.P. Betulinic acid, a natural compound with potent anticancer effects. Anticancer Drugs, 2010, 21(3), 215-227.
[http://dx.doi.org/10.1097/CAD.0b013e3283357c62] [PMID: 20075711]
[15]
Ghaffari Moghaddam, M.; Bin, H. Ahmad, F.; Samzadeh-Kermani, A. Biological activity of betulinic acid: A review. Pharmacol. Pharm., 2012, 03(02), 119-123.
[http://dx.doi.org/10.4236/pp.2012.32018]
[16]
Yang, C.; Li, Y.; Fu, L.; Jiang, T.; Meng, F. Betulinic acid induces apoptosis and inhibits metastasis of human renal carcinoma cells in vitro and in vivo. J. Cell. Biochem., 2018, 119(10), 8611-8622.
[http://dx.doi.org/10.1002/jcb.27116] [PMID: 29923216]
[17]
Saneja, A.; Kumar, R.; Singh, A.; Dhar Dubey, R.; Mintoo, M.J.; Singh, G.; Mondhe, D.M.; Panda, A.K.; Gupta, P.N. Development and evaluation of long-circulating nanoparticles loaded with betulinic acid for improved anti-tumor efficacy. Int. J. Pharm., 2017, 531(1), 153-166.
[http://dx.doi.org/10.1016/j.ijpharm.2017.08.076] [PMID: 28823888]
[18]
Cai, Y.; Zheng, Y.; Gu, J.; Wang, S.; Wang, N.; Yang, B.; Zhang, F.; Wang, D.; Fu, W.; Wang, Z. Betulinic acid chemosensitizes breast cancer by triggering ER stress-mediated apoptosis by directly targeting GRP78. Cell Death Dis., 2018, 9(6), 636.
[http://dx.doi.org/10.1038/s41419-018-0669-8] [PMID: 29802332]
[19]
Goswami, P.; Paul, S.; Banerjee, R.; Kundu, R.; Mukherjee, A. Betulinic acid induces DNA damage and apoptosis in SiHa cells. Mutat. Res. Genet. Toxicol. Environ. Mutagen., 2018, 828, 1-9.
[http://dx.doi.org/10.1016/j.mrgentox.2018.02.003] [PMID: 29555058]
[20]
Fulda, S.; Kroemer, G. Targeting mitochondrial apoptosis by betulinic acid in human cancers. Drug Discov. Today, 2009, 14(17-18), 885-890.
[http://dx.doi.org/10.1016/j.drudis.2009.05.015] [PMID: 19520182]
[21]
Seo, J.; Jung, J.; Jang, D.S.; Kim, J.; Kim, J.H. Induction of cell death by betulinic acid through induction of apoptosis and inhibition of autophagic flux in microglia BV-2 cells. Biomol. Ther. (Seoul), 2017, 25(6), 618-624.
[http://dx.doi.org/10.4062/biomolther.2016.255] [PMID: 28274097]
[22]
Wang, X.; Lu, X.; Zhu, R.; Zhang, K.; Li, S.; Chen, Z.; Li, L. Betulinic acid induces apoptosis in differentiated PC12 cells via ROS-mediated mitochondrial pathway. Neurochem. Res., 2017, 42(4), 1130-1140.
[http://dx.doi.org/10.1007/s11064-016-2147-y] [PMID: 28124213]
[23]
Wang, S.; Wang, K.; Zhang, C.; Zhang, W.; Xu, Q.; Wang, Y.; Zhang, Y.; Li, Y.; Zhang, Y.; Zhu, H.; Song, F.; Lei, Y.; Bu, Y. Overaccumulation of p53-mediated autophagy protects against betulinic acid-induced apoptotic cell death in colorectal cancer cells. Cell Death Dis., 2017, 8(10) e3087
[http://dx.doi.org/10.1038/cddis.2017.485] [PMID: 28981110]
[24]
Shankar, E.; Zhang, A.; Franco, D.; Gupta, S. Betulinic acid-mediated apoptosis in human prostate cancer cells involves p53 and nuclear factor-kappa B (NF-κB) pathways. Molecules, 2017, 22(2), 264.
[http://dx.doi.org/10.3390/molecules22020264] [PMID: 28208611]
[25]
Jin, K.S.; Oh, Y.N.; Hyun, S.K.; Kwon, H.J.; Kim, B.W. Betulinic acid isolated from Vitis amurensis root inhibits 3-isobutyl-1-methylxanthine induced melanogenesis via the regulation of MEK/ERK and PI3K/Akt pathways in B16F10 cells. Food Chem. Toxicol., 2014, 68, 38-43.
[http://dx.doi.org/10.1016/j.fct.2014.03.001] [PMID: 24632067]
[26]
Saeed, M.E.M.; Mahmoud, N.; Sugimoto, Y.; Efferth, T.; Abdel-Aziz, H. Betulinic acid exerts cytotoxic activity against multidrug-resistant tumor cells via targeting autocrine motility factor receptor (AMFR). Front. Pharmacol., 2018, 9, 481.
[http://dx.doi.org/10.3389/fphar.2018.00481] [PMID: 29867487]
[27]
Waechter, F.; da Silva, G.N.S.; Willig, J.B.; de Oliveira, C.B.; Vieira, B.D.; Trivella, D.B.B.; Zimmer, A.R.; Buffon, A.; Pilger, D.A.; Gnoatto, S.C.B. Design, synthesis and biological evaluation of betulinic acid derivatives as new antitumor agents for leukemia. Anticancer. Agents Med. Chem., 2017, 17(13), 1777-1785.
[PMID: 28403779]
[28]
Ravishankar, D.; Rajora, A.K.; Greco, F.; Osborn, H.M.I. Flavonoids as prospective compounds for anti-cancer therapy. Int. J. Biochem. Cell Biol., 2013, 45(12), 2821-2831.
[http://dx.doi.org/10.1016/j.biocel.2013.10.004] [PMID: 24128857]
[29]
Erdogan, S.; Turkekul, K.; Serttas, R.; Erdogan, Z. The natural flavonoid apigenin sensitizes human CD44+ prostate cancer stem cells to cisplatin therapy. Biomed. Pharmacother., 2017, 88, 210-217.
[http://dx.doi.org/10.1016/j.biopha.2017.01.056] [PMID: 28107698]
[30]
Wu, Q.; Kroon, P.A.; Shao, H.; Needs, P.W.; Yang, X. Differential effects of quercetin and two of its derivatives, isorhamnetin and isorhamnetin-3-glucuronide, in inhibiting the proliferation of human breast-cancer MCF-7 cells. J. Agric. Food Chem., 2018, 66(27), 7181-7189.
[http://dx.doi.org/10.1021/acs.jafc.8b02420] [PMID: 29905475]
[31]
Dury, L.; Nasr, R.; Lorendeau, D.; Comsa, E.; Wong, I.; Zhu, X.; Chan, K-F.; Chan, T-H.; Chow, L.; Falson, P.; Di Pietro, A.; Baubichon-Cortay, H. Flavonoid dimers are highly potent killers of multidrug resistant cancer cells overexpressing MRP1. Biochem. Pharmacol., 2017, 124, 10-18.
[http://dx.doi.org/10.1016/j.bcp.2016.10.013] [PMID: 27984000]
[32]
Arumuggam, N.; Melong, N.; Too, C.K.; Berman, J.N.; Rupasinghe, H.V. Phloridzin docosahexaenoate, a novel flavonoid derivative, suppresses growth and induces apoptosis in T-cell acute lymphoblastic leukemia cells. Am. J. Cancer Res., 2017, 7(12), 2452-2464.
[PMID: 29312799]
[33]
Lin, J-A.; Wu, C-H.; Yen, G-C. Breadfruit flavonoid derivatives attenuate advanced glycation end products (AGEs)-enhanced colon malignancy in HCT116 cancer cells. J. Funct. Foods, 2017, 31, 248-254.
[http://dx.doi.org/10.1016/j.jff.2017.01.050]
[34]
Yasuda, M.T.; Sakakibara, H.; Shimoi, K. Estrogen- and stress-induced DNA damage in breast cancer and chemoprevention with dietary flavonoid. Genes Environ., 2017, 39(1), 10.
[http://dx.doi.org/10.1186/s41021-016-0071-7] [PMID: 28163803]
[35]
Youns, M.; Abdel Halim Hegazy, W. The natural flavonoid fisetin inhibits cellular proliferation of hepatic, colorectal, and pancreatic cancer cells through modulation of multiple signaling pathways. PLoS One, 2017, 12(1) e0169335
[http://dx.doi.org/10.1371/journal.pone.0169335] [PMID: 28052097]
[36]
Torres, S.L.; Arruda, M.S.P.; Arruda, A.C.; Müller, A.H.; Silva, S.C. Flavonoids from Brosimum acutifolium. Phytochemistry, 2000, 53(8), 1047-1050.
[http://dx.doi.org/10.1016/S0031-9422(99)00608-1] [PMID: 10820829]
[37]
Takashima, J.; Ohsaki, A. Brosimacutins A-I, nine new flavonoids from Brosimum acutifolium. J. Nat. Prod., 2002, 65(12), 1843-1847.
[http://dx.doi.org/10.1021/np020241f] [PMID: 12502325]
[38]
Keßberg, A.; Metz, P. Utilizing an O-quinone methide in asymmetric transfer hydrogenation: enantioselective synthesis of brosimine a, brosimine b, and brosimacutin l. Angew. Chem. Int. Ed. Engl., 2016, 55(3), 1160-1163.
[http://dx.doi.org/10.1002/anie.201507269] [PMID: 26634801]
[39]
Torres, S.L.; Monteiro, J.C.M.; Arruda, M.S.P.; Müller, A.H.; Arruda, A.C. Two flavans from Brosimum acutifolium. Phytochemistry, 1997, 44(2), 347-349.
[http://dx.doi.org/10.1016/S0031-9422(96)00447-5]
[40]
Rajpert-De Meyts, E.; Skotheim, R.I. Complex polygenic nature of testicular germ cell cancer suggests multifactorial aetiology. Eur. Urol., 2018, 73(6), 832-833.
[http://dx.doi.org/10.1016/j.eururo.2018.02.023] [PMID: 29530636]
[41]
Terrazzino, S.; Deantonio, L.; Cargnin, S.; Donis, L.; Pisani, C.; Masini, L.; Gambaro, G.; Canonico, P.L.; Genazzani, A.A.; Krengli, M. DNA methyltransferase gene polymorphisms for prediction of radiation-induced skin fibrosis after treatment of breast cancer: a multifactorial genetic approach. Cancer Res. Treat., 2017, 49(2), 464-472.
[http://dx.doi.org/10.4143/crt.2016.256] [PMID: 27554481]
[42]
Casarini, L.; Marino, M.; Nuzzo, F.; Simoni, M.; Brigante, G. A statistical, in silico model predicts polygenic thyroid cancer risk. Endocr. Abstr., 2017.
[http://dx.doi.org/10.1530/endoabs.49.GP245]
[43]
Gong, C-X.; Liu, F.; Iqbal, K. Multifactorial hypothesis and multi-targets for Alzheimer’s disease. J. Alzheimers Dis., 2018, 64(s1), S107-S117.
[http://dx.doi.org/10.3233/JAD-179921] [PMID: 29562523]
[44]
Njogu, P.M.; Okombo, J.; Chibale, K. Designed hybrid compounds for tropical parasitic diseases; Des. Hybrid Mol. Drug Dev, 2017, pp. 83-135.
[http://dx.doi.org/10.1016/B978-0-08-101011-2.00004-0]
[45]
Uliassi, E.; Prati, F.; Bongarzone, S.; Bolognesi, M.L. Medicinal chemistry of hybrids for neurodegenerative diseases; Des. Hybrid Mol. Drug Dev, 2017, pp. 259-277.
[http://dx.doi.org/10.1016/B978-0-08-101011-2.00010-6]
[46]
Nepali, K.; Sharma, S.; Sharma, M.; Bedi, P.M.S.; Dhar, K.L. Rational approaches, design strategies, structure activity relationship and mechanistic insights for anticancer hybrids. Eur. J. Med. Chem., 2014, 77, 422-487.
[http://dx.doi.org/10.1016/j.ejmech.2014.03.018] [PMID: 24685980]
[47]
Kucuksayan, E.; Ozben, T. Hybrid compounds as multitarget directed anticancer agents. Curr. Top. Med. Chem., 2017, 17(8), 907-918.
[http://dx.doi.org/10.2174/1568026616666160927155515] [PMID: 27697050]
[48]
Kerru, N.; Singh, P.; Koorbanally, N.; Raj, R.; Kumar, V. Recent advances (2015-2016) in anticancer hybrids. Eur. J. Med. Chem., 2017, 142, 179-212.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.033] [PMID: 28760313]
[49]
da Silva, G.N.S.; Maria, N.R.G.; Schuck, D.C.; Cruz, L.N.; de Moraes, M.S.; Nakabashi, M.; Graebin, C.; Gosmann, G.; Garcia, C.R.S.; Gnoatto, S.C.B. Two series of new semisynthetic triterpene derivatives: differences in anti-malarial activity, cytotoxicity and mechanism of action. Malar. J., 2013, 12(1), 89.
[http://dx.doi.org/10.1186/1475-2875-12-89] [PMID: 23497003]
[50]
Innocente, A.M.; Silva, G.N.; Cruz, L.N.; Moraes, M.S.; Nakabashi, M.; Sonnet, P.; Gosmann, G.; Garcia, C.R.; Gnoatto, S.C. Synthesis and antiplasmodial activity of betulinic acid and ursolic acid analogues. Molecules, 2012, 17(10), 12003-12014.
[http://dx.doi.org/10.3390/molecules171012003] [PMID: 23085651]
[51]
Haque, A.; Siddiqi, M.; Rahman, A. M.; Chowdhury, A. S. Isolation of Betulinic Acid and 2,3-Dihydroxyolean-12-en-28-oic Acid from the Leaves of Callistemon linearis. Bangladesh Journals On- Line, 2013, 61(2)
[52]
Teixeira, A.F.; Alcantara, A.F. de C.; Pilo-Veloso, D. Structure determination by 1H and 13C NMR of a new flavan isolated from Brosimum acutifolium: 4′,7-dihydroxy-8-prenylflavan. Magn. Reson. Chem., 2000, 38(4), 301-304.
[http://dx.doi.org/10.1002/(SICI)1097-458X(200004)38:4<301:AID-MRC632>3.0.CO;2-T]
[53]
Gnoatto, S.C.B.; Susplugas, S.; Vechia, L.D.; Ferreira, T.B.; Dassonville-Klimpt, A.; Zimmer, K.R.; Demailly, C.; Da Nascimento, S.; Guillon, J.; Grellier, P. Pharmacomodulation on the 3-acetylursolic acid skeleton: Design, synthesis, and biological evaluation of novel N-3-[4-(3-aminopropyl)piperazinyl]propyl-3-O-acetylursolamide derivatives as antimalarial agents. Bioorg. Med. Chem., 2008, 16(2), 771-782.
[http://dx.doi.org/10.1016/j.bmc.2007.10.031] [PMID: 17967541]
[54]
Neises, B.; Steglich, W. Simple method for the esterification of carboxylic acids. Angew. Chem. Int. Ed. Engl., 1978, 17(7), 522-524.
[http://dx.doi.org/10.1002/anie.197805221]
[55]
Haque, A.; Siddiqi, M. M. A.; Rahman, A. M.; Hasan, C. M.; Chowdhury, A. S. Isolation of betulinic acid and 2,3- dihydroxyolean-12-en-28-oic acid from the leaves of Callistemon linearis. Dhaka Univ. J. Sci., 2013, 61(2)
[56]
Reddy, C.R.; Krishna, G.; Reddy, M.D. Synthesis of substituted 3-furanoates from MBH-acetates of acetylenic aldehydes via tandem isomerization-deacetylation-cycloisomerization: access to Elliott’s alcohol. Org. Biomol. Chem., 2014, 12(10), 1664-1670.
[http://dx.doi.org/10.1039/c3ob42396d] [PMID: 24492976]
[57]
Mazimba, O.; Masesane, I.B.; Majinda, R.R. An efficient synthesis of flavans from salicylaldehyde and acetophenone derivatives. Tetrahedron Lett., 2011, 52(50), 6716-6718.
[http://dx.doi.org/10.1016/j.tetlet.2011.09.147]
[58]
Cargnin, S. T.; Staudt, A. F.; Paula De Azevedo Dos Santos, A.; Gosmann, G.; Bioni, C.; Teles, G.; Gnoatto, S. B. Effective approach to semi-synthesis of lupane and ursane brominated derivatives and its effects on viability of Leishmania amazonensis. Ann Med Chem Res., 2017, 3(1)
[59]
Gilles, V.; Vieira, M.A.; Lacerda, V., Jr; Castro, E.V.R.; Santos, R.B.; Orestes, E.; Carneiro, J.W.M.; Greco, S.J.; Gilles, V.; Vieira, M.A. A new, simple and efficient method of Steglich esterification of juglone with long-chain fatty acids: synthesis of a new class of non-polymeric wax deposition inhibitors for crude oil. J. Braz. Chem. Soc., 2014, 26(1), 74-83.
[http://dx.doi.org/10.5935/0103-5053.20140216]
[60]
Fallahi-Sichani, M.; Honarnejad, S.; Heiser, L.M.; Gray, J.W.; Sorger, P.K. Metrics other than potency reveal systematic variation in responses to cancer drugs. Nat. Chem. Biol., 2013, 9(11), 708-714.
[http://dx.doi.org/10.1038/nchembio.1337] [PMID: 24013279]
[61]
Hafner, M.; Niepel, M.; Chung, M.; Sorger, P.K. Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs. Nat. Methods, 2016, 13(6), 521-527.
[http://dx.doi.org/10.1038/nmeth.3853] [PMID: 27135972]
[62]
Perelson, A.S.; Deeks, S.G. Drug effectiveness explained: the mathematics of antiviral agents for HIV. Sci. Transl. Med., 2011, 3(91) 91ps30
[http://dx.doi.org/10.1126/scitranslmed.3002656] [PMID: 21753120]
[63]
Calhelha, R.C.; Martínez, M.A.; Prieto, M.A.; Ferreira, I.C.F.R. Mathematical models of cytotoxic effects in endpoint tumor cell line assays: critical assessment of the application of a single parametric value as a standard criterion to quantify the dose-response effects and new unexplored proposal formats. Analyst (Lond.), 2017, 142(21), 4124-4141.
[http://dx.doi.org/10.1039/C7AN00782E] [PMID: 28991301]
[64]
Damle, A.A.; Pawar, Y.P.; Narkar, A.A. Anticancer activity of betulinic acid on MCF-7 tumors in nude mice. Indian J. Exp. Biol., 2013, 51(7), 485-491.
[PMID: 23898546]
[65]
Sun, Y-F.; Song, C-K.; Viernstein, H.; Unger, F.; Liang, Z-S. Apoptosis of human breast cancer cells induced by microencapsulated betulinic acid from sour jujube fruits through the mitochondria transduction pathway. Food Chem., 2013, 138(2-3), 1998-2007.
[http://dx.doi.org/10.1016/j.foodchem.2012.10.079] [PMID: 23411336]
[66]
Xu, T.; Pang, Q.; Zhou, D.; Zhang, A.; Luo, S.; Wang, Y.; Yan, X. Proteomic investigation into betulinic acid-induced apoptosis of human cervical cancer HeLa cells. PLoS One, 2014, 9(8) e105768
[http://dx.doi.org/10.1371/journal.pone.0105768] [PMID: 25148076]
[67]
Aponte, J.C.; Vaisberg, A.J.; Rojas, R.; Caviedes, L.; Lewis, W.H.; Lamas, G.; Sarasara, C.; Gilman, R.H.; Hammond, G.B. Isolation of cytotoxic metabolites from targeted peruvian amazonian medicinal plants. J. Nat. Prod., 2008, 71(1), 102-105.
[http://dx.doi.org/10.1021/np070560c] [PMID: 18163590]
[68]
Ngemenya, M.N.; Abwenzoh, G.N.; Ikome, H.N.; Zofou, D.; Ntie-Kang, F.; Efange, S.M.N. Structurally simple synthetic 1, 4-disubstituted piperidines with high selectivity for resistant Plasmodium falciparum. BMC Pharmacol. Toxicol., 2018, 19(1), 42.
[http://dx.doi.org/10.1186/s40360-018-0233-2] [PMID: 29973275]
[69]
Chuprajob, T.; Changtam, C.; Chokchaisiri, R.; Chunglok, W.; Sornkaew, N.; Suksamrarn, A. Synthesis, cytotoxicity against human oral cancer KB cells and structure-activity relationship studies of trienone analogues of curcuminoids. Bioorg. Med. Chem. Lett., 2014, 24(13), 2839-2844.
[http://dx.doi.org/10.1016/j.bmcl.2014.04.105] [PMID: 24857542]
[70]
Foo, J.B.; Saiful Yazan, L.; Tor, Y.S.; Wibowo, A.; Ismail, N.; How, C.W.; Armania, N.; Loh, S.P.; Ismail, I.S.; Cheah, Y.K.; Abdullah, R. Induction of cell cycle arrest and apoptosis by betulinic acid-rich fraction from Dillenia suffruticosa root in MCF-7 cells involved p53/p21 and mitochondrial signalling pathway. J. Ethnopharmacol., 2015, 166, 270-278.
[http://dx.doi.org/10.1016/j.jep.2015.03.039] [PMID: 25797115]
[71]
Herrera, F.; Martin, V.; Carrera, P.; García-Santos, G.; Rodriguez-Blanco, J.; Rodriguez, C.; Antolín, I. Tryptamine induces cell death with ultrastructural features of autophagy in neurons and glia: Possible relevance for neurodegenerative disorders. Anat. Rec. Part A Discov. Mol. Cell. Evol. Biol., 2006, 288A(9), 1026-1030.
[72]
Doonan, F.; Cotter, T.G. Morphological assessment of apoptosis. Methods, 2008, 44(3), 200-204.
[http://dx.doi.org/10.1016/j.ymeth.2007.11.006] [PMID: 18314050]
[73]
Tixeira, R.; Caruso, S.; Paone, S.; Baxter, A.A.; Atkin-Smith, G.K.; Hulett, M.D.; Poon, I.K.H. Defining the morphologic features and products of cell disassembly during apoptosis. Apoptosis, 2017, 22(3), 475-477.
[http://dx.doi.org/10.1007/s10495-017-1345-7] [PMID: 28102458]
[74]
Atkin-Smith, G.K.; Poon, I.K.H. Disassembly of the dying: mechanisms and functions. Trends Cell Biol., 2017, 27(2), 151-162.
[http://dx.doi.org/10.1016/j.tcb.2016.08.011] [PMID: 27647018]
[75]
Henry, C.M.; Hollville, E.; Martin, S.J. Measuring apoptosis by microscopy and flow cytometry. Methods, 2013, 61(2), 90-97.
[http://dx.doi.org/10.1016/j.ymeth.2013.01.008] [PMID: 23403105]
[76]
Chung, S-H.; Franceschi, S.; Lambert, P.F. Estrogen and ERalpha: culprits in cervical cancer? Trends Endocrinol. Metab., 2010, 21(8), 504-511.
[http://dx.doi.org/10.1016/j.tem.2010.03.005] [PMID: 20456973]
[77]
Tzenov, Y.R.; Andrews, P.; Voisey, K.; Gai, L.; Carter, B.; Whelan, K.; Popadiuk, C.; Kao, K.R. Selective estrogen receptor modulators and betulinic acid act synergistically to target ERα and SP1 transcription factor dependent Pygopus expression in breast cancer. J. Clin. Pathol., 2016, 69(6), 518-526.
[http://dx.doi.org/10.1136/jclinpath-2015-203395] [PMID: 26645832]
[78]
Kim, H-I.; Quan, F-S.; Kim, J-E.; Lee, N-R.; Kim, H.J.; Jo, S.J.; Lee, C-M.; Jang, D.S.; Inn, K-S. Inhibition of estrogen signaling through depletion of estrogen receptor alpha by ursolic acid and betulinic acid from Prunella vulgaris var. lilacina. Biochem. Biophys. Res. Commun., 2014, 451(2), 282-287.
[http://dx.doi.org/10.1016/j.bbrc.2014.07.115] [PMID: 25088993]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 5
Year: 2020
Page: [622 - 633]
Pages: 12
DOI: 10.2174/1871520620666200124111634
Price: $65

Article Metrics

PDF: 15
HTML: 3
EPUB: 1
PRC: 1