Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Novel Suberoylanilide Hydroxamic Acid Analogs Inhibit Angiogenesis and Induce Apoptosis in Breast Cancer Cells

Author(s): Gopikrishna Moku*, Swathi Vangala, Venu Yakati, Chaitanya C. Gali, Soumen Saha, Vijay S. Madamsetty and Amber Vyas

Volume 22, Issue 5, 2022

Published on: 03 January, 2022

Page: [914 - 925] Pages: 12

DOI: 10.2174/1871520621666210901102425

Price: $65

Abstract

Background: Histone deacetylases (HDACs) are the enzymes that catalyze the removal of the acetyl group from lysine residues and regulate several biological processes. Suberoylanilide hydroxamic acid (SAHA) is a notable HDAC inhibitor that exhibited remarkable anti-proliferative efficiency by alleviating gene regulation against solid and hematologic cancers.

Aim: The aim of this study was to develop new chemotherapeutic agents for breast cancer treatment, therefore, a novel series of Suberoylanilide hydroxamic acid (SAHA) analogs were investigated as anticancer agents.

Methods: We designed and synthesized a novel series of analogs derived from SAHA by substituting alkyl, alkoxy, halo, and benzyl groups at different positions of the phenyl ring. The newly synthesized analogs were assessed for their cytotoxic potential against four human cancer cell lines in comparison with healthy cell lines, using several biological assays.

Results: SAHA analogs displayed significant cytotoxic potential with IC50 values ranging from 1.6 to 19.2 μM in various tumor cell lines. Among these analogs, 2d (containing 3-chloro, 4-floro substitutions on phenyl moiety), 2h (containing 3,4-di chloro substitutions on phenyl moiety), and 2j (containing 4-chloro, 3-methyl substitutions on phenyl moiety) showed significant cytotoxic potential with IC50 values ranging from 1.6 to 1.8 μM in MCF-7 (breast carcinoma) cell line. More importantly, these analogs were found to be non-toxic towards healthy primary human hepatocytes (PHH) and mouse fibroblast cells (NIH3T3), which represent their tumor selectivity. These analogs were further analyzed for their effect on cell migration, BrdU incorporation, Annexin V-FITC and cell cycle arrest (Sub-G1 phase). Remarkably, analogs 2d, 2h, and 2j displayed significant HDAC inhibition than the parent SAHA molecule. Further studies also confirmed that these SAHA analogs are efficient in inducing apoptosis, as they regulated the expression of several proteins involved in mitochondrial or intrinsic apoptosis pathways. Findings in the Chick Chorioallantoic Membrane (CAM) assay studies revealed anti-angiogenic properties of the currently described SAHA analogs.

Conclusion: From anti-proliferative study results, it is clearly evident that 3,4-substitution at the SAHA phenyl ring improves the anti-proliferative activity of SAHA. Based on these findings, we presume that the synthesized novel SAHA analogs could be potential therapeutic agents in treating breast cancer.

Keywords: Angiogenesis, anti-cancer activity, apoptosis, cell cycle arrest, HDAC inhibitors, SAHA analogs.

« Previous Next »
Graphical Abstract

[1]
Singh, R.K.; Kumar, S.; Prasad, D.N.; Bhardwaj, T.R. Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives. Eur. J. Med. Chem., 2018, 151, 401-433.
[http://dx.doi.org/10.1016/j.ejmech.2018.04.001] [PMID: 29649739]
[2]
Krishnan, V.; Rajasekaran, A.K. Clinical nanomedicine: a solution to the chemotherapy conundrum in pediatric leukemia therapy. Clin. Pharmacol. Ther., 2014, 95(2), 168-178.
[http://dx.doi.org/10.1038/clpt.2013.174] [PMID: 24013811]
[3]
Krukiewicz, K.; Zak, J.K. Biomaterial-based regional chemotherapy: Local anticancer drug delivery to enhance chemotherapy and minimize its side-effects. Mater. Sci. Eng. C, 2016, 62, 927-942.
[http://dx.doi.org/10.1016/j.msec.2016.01.063] [PMID: 26952500]
[4]
Markman, J.L.; Rekechenetskiy, A.; Holler, E.; Ljubimova, J.Y. Nanomedicine therapeutic approaches to overcome cancer drug resistance. Adv. Drug Deliv. Rev., 2013, 65(13-14), 1866-1879.
[http://dx.doi.org/10.1016/j.addr.2013.09.019] [PMID: 24120656]
[5]
Walsh, C.T.; Garneau-Tsodikova, S.; Gatto, G.J. Jr Protein posttranslational modifications: the chemistry of proteome diversifications. Angew. Chem. Int. Ed., 2005, 44(45), 7342-7372.
[http://dx.doi.org/10.1002/anie.200501023] [PMID: 16267872]
[6]
Gregoretti, I.V.; Lee, Y.M.; Goodson, H.V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol., 2004, 338(1), 17-31.
[http://dx.doi.org/10.1016/j.jmb.2004.02.006] [PMID: 15050820]
[7]
Glozak, M.A.; Seto, E. Histone deacetylases and cancer. Oncogene, 2007, 26(37), 5420-5432.
[http://dx.doi.org/10.1038/sj.onc.1210610] [PMID: 17694083]
[8]
Chuang, C.; Pan, J.; Hawke, D.H.; Lin, S.H.; Yu-Lee, L. Acetylation of RNA processing proteins and cell cycle proteins in mitosis. PLoS One, 2013, 8, e73841.
[http://dx.doi.org/10.1371/journal.pone.0073841] [PMID: 24069238]
[9]
Newbold, A.; Salmon, J.M.; Martin, B.P.; Stanley, K.; Johnstone, R.W. The role of p21(waf1/cip1) and p27(Kip1) in HDACi-mediated tumor cell death and cell cycle arrest in the Eμ-myc model of B-cell lymphoma. Oncogene, 2014, 33(47), 5415-5423.
[http://dx.doi.org/10.1038/onc.2013.482] [PMID: 24292681]
[10]
Marks, P.A. Histone deacetylase inhibitors: a chemical genetics approach to understanding cellular functions. Biochim. Biophys. Acta, 2010, 1799(10-12), 717-725.
[http://dx.doi.org/10.1016/j.bbagrm.2010.05.008] [PMID: 20594930]
[11]
Warrell, R.P., Jr; He, L.Z.; Richon, V.; Calleja, E.; Pandolfi, P.P. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J. Natl. Cancer Inst., 1998, 90(21), 1621-1625.
[http://dx.doi.org/10.1093/jnci/90.21.1621] [PMID: 9811311]
[12]
Grant, S.; Easley, C.; Kirkpatrick, P. Vorinostat. Nat. Rev. Drug Discov., 2007, 6(1), 21-22.
[http://dx.doi.org/10.1038/nrd2227] [PMID: 17269160]
[13]
Plumb, J.A.; Finn, P.W.; Williams, R.J.; Bandara, M.J.; Romero, M.R.; Watkins, C.J.; La Thangue, N.B.; Brown, R. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol. Cancer Ther., 2003, 2(8), 721-728.
[PMID: 12939461]
[14]
Laubach, J.P.; Moreau, P.; San-Miguel, J.F.; Richardson, P.G. Panobinostat for the treatment of multiple myeloma. Clin. Cancer Res., 2015, 21(21), 4767-4773.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-0530] [PMID: 26362997]
[15]
Rosato, R.R.; Almenara, J.A.; Dai, Y.; Grant, S. Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. Mol. Cancer Ther., 2003, 2(12), 1273-1284.
[PMID: 14707268]
[16]
Darvas, K.; Rosenberger, S.; Brenner, D.; Fritsch, C.; Gmelin, N.; Krammer, P.H.; Rösl, F. Histone deacetylase inhibitor-induced sensitization to TNFalpha/TRAIL-mediated apoptosis in cervical carcinoma cells is dependent on HPV oncogene expression. Int. J. Cancer, 2010, 127(6), 1384-1392.
[http://dx.doi.org/10.1002/ijc.25170] [PMID: 20087862]
[17]
Srinivas, C.; Swathi, V.; Priyanka, C.; Anjana Devi, T.; Subba Reddy, B.V.; Janaki Ramaiah, M.; Bhadra, U.; Bhadra, M.P. Novel SAHA analogues inhibit HDACs, induce apoptosis and modulate the expression of microRNAs in hepatocellular carcinoma. Apoptosis, 2016, 21(11), 1249-1264.
[http://dx.doi.org/10.1007/s10495-016-1278-6] [PMID: 27502208]
[18]
Krammer, P.H.; Kamiński, M.; Kiessling, M.; Gülow, K. No life without death. Adv. Cancer Res., 2007, 97, 111-138.
[http://dx.doi.org/10.1016/S0065-230X(06)97005-5] [PMID: 17419943]
[19]
Walczak, H.; Haas, T.L. Biochemical analysis of the native TRAIL death-inducing signaling complex. Methods Mol. Biol., 2008, 414, 221-239.
[http://dx.doi.org/10.1007/978-1-59745-339-4_16] [PMID: 18175822]
[20]
Jazirehi, A.R.; Arle, D. Epigenetic regulation of the TRAIL/Apo2L apoptotic pathway by histone deacetylase inhibitors: an attractive approach to bypass melanoma immunotherapy resistance. Am. J. Clin. Exp. Immunol., 2013, 2(1), 55-74.
[PMID: 23885325]
[21]
Reed, J.C. Bcl-2-family proteins and hematologic malignancies: history and future prospects. Blood, 2008, 111(7), 3322-3330.
[http://dx.doi.org/10.1182/blood-2007-09-078162] [PMID: 18362212]
[22]
Gediya, L.K.; Chopra, P.; Purushottamachar, P.; Maheshwari, N.; Njar, V.C.O. A new simple and high-yield synthesis of suberoylanilide hydroxamic acid and its inhibitory effect alone or in combination with retinoids on proliferation of human prostate cancer cells. J. Med. Chem., 2005, 48(15), 5047-5051.
[23]
Fan, H.; Zhang, R.; Tesfaye, D.; Tholen, E.; Looft, C.; Hölker, M.; Schellander, K.; Cinar, M.U. Sulforaphane causes a major epigenetic repression of myostatin in porcine satellite cells. Epigenetics, 2012, 7(12), 1379-1390.
[http://dx.doi.org/10.4161/epi.22609] [PMID: 23092945]
[24]
Luu, T.H.; Morgan, R.J.; Leong, L.; Lim, D.; McNamara, M.; Portnow, J.; Frankel, P.; Smith, D.D.; Doroshow, J.H.; Wong, C.; Aparicio, A.; Gandara, D.R.; Somlo, G. A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California cancer consortium study. Clin. Cancer Res., 2008, 14(21), 7138-7142.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-0122] [PMID: 18981013]
[25]
Wozniak, M.B.; Villuendas, R.; Bischoff, J.R.; Aparicio, C.B.; Martínez Leal, J.F.; de La Cueva, P.; Rodriguez, M.E.; Herreros, B.; Martin-Perez, D.; Longo, M.I.; Herrera, M.; Piris, M.A.; Ortiz-Romero, P.L. Vorinostat interferes with the signaling transduction pathway of T-cell receptor and synergizes with phosphoinositide-3 kinase inhibitors in cutaneous T-cell lymphoma. Haematologica, 2010, 95(4), 613-621.
[http://dx.doi.org/10.3324/haematol.2009.013870] [PMID: 20133897]
[26]
Xu, W.S.; Parmigiani, R.B.; Marks, P.A. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene, 2007, 26(37), 5541-5552.
[http://dx.doi.org/10.1038/sj.onc.1210620] [PMID: 17694093]
[27]
Schrump, D.S. Cytotoxicity mediated by histone deacetylase inhibitors in cancer cells: mechanisms and potential clinical implications. Clin. Cancer Res., 2009, 15(12), 3947-3957.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-2787] [PMID: 19509170]
[28]
Anto, R.J.; Mukhopadhyay, A.; Denning, K.; Aggarwal, B.B. Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. Carcinogenesis, 2002, 23(1), 143-150.
[http://dx.doi.org/10.1093/carcin/23.1.143] [PMID: 11756235]
[29]
Garu, A.; Moku, G.; Gulla, S.K.; Pramanik, D.; Majeti, B.K.; Karmali, P.P.; Shaik, H.; Sreedhar, B.; Chaudhuri, A. Examples of tumor growth inhibition properties of liposomal formulations of pH-sensitive histidinylated cationic amphiphiles. ACS Biomater. Sci. Eng., 2015, 1(8), 646-655.
[http://dx.doi.org/10.1021/acsbiomaterials.5b00025] [PMID: 33435088]
[30]
Al-Yacoub, N.; Fecker, L.F.; Möbs, M.; Plötz, M.; Braun, F.K.; Sterry, W.; Eberle, J. Apoptosis induction by SAHA in cutaneous T-cell lymphoma cells is related to downregulation of c-FLIP and enhanced TRAIL signaling. J. Invest. Dermatol., 2012, 132(9), 2263-2274.
[http://dx.doi.org/10.1038/jid.2012.125] [PMID: 22551975]
[31]
Moku, G.; Gulla, S.K.; Nimmu, N.V.; Khalid, S.; Chaudhuri, A. Delivering anti-cancer drugs with endosomal pH-sensitive anti-cancer liposomes. Biomater. Sci., 2016, 4(4), 627-638.
[http://dx.doi.org/10.1039/C5BM00479A] [PMID: 26806172]
[32]
Li, J.; Yuan, J. Caspases in apoptosis and beyond. Oncogene, 2008, 27(48), 6194-6206.
[http://dx.doi.org/10.1038/onc.2008.297] [PMID: 18931687]
[33]
Fouad, Y.A.; Aanei, C. Revisiting the hallmarks of cancer. Am. J. Cancer Res., 2017, 7(5), 1016-1036.
[PMID: 28560055]

Rights & Permissions Print Cite
Article Metrics
20
1
© 2024 Bentham Science Publishers | Privacy Policy