Small Molecular Leads Differentially Active Against HER2 Positive and Triple Negative Breast Cancer Cell Lines

Author(s): Adnan Badran*, Atia-tul-Wahab*, Sharmeen Fayyaz, Elias Baydoun, Muhammad Iqbal Choudhary*.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 7 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Breast cancer is the most prevalent cancer type in women globally. It is characterized by distinct subtypes depending on different gene expression patterns. Oncogene HER2 is expressed on the surface of cell and is responsible for cell growth regulation. Increase in HER2 receptor protein due to gene amplification, results in aggressive growth, and high metastasis in cancer cells.

Methods: The current study evaluates and compares the anti-breast cancer effect of commercially available compounds against HER2 overexpressing BT-474, and triple negative MDA-MB-231 breast cancer cell lines.

Results: Preliminary in vitro cell viability assays on these cell lines identified 6 lead molecules active against breast cancer. Convallatoxin (4), a steroidal lactone glycoside, showed the most potent activity with IC50 values of 0.63 ± 0.56, and 0.69 ± 0.59 µM against BT-474 and MDA-MB-231, respectively, whereas 4-[4-(Trifluoromethyl)-phenoxy] phenol (3) a phenol derivative, and Reserpine (5) an indole alkaloid selectively inhibited the growth of BT-474, and MDA-MB-231 breast cancer cells, respectively.

Conclusion: These results exhibited the potential of small molecules in the treatment of HER2 amplified and triple negative breast cancers in vitro.

Keywords: Anti-cancer, breast cancer, Human Epidermal Growth Factor Receptor-2 (HER2), estrogen receptors, heterocyclic compounds, convallatoxin.

[1]
Ruiz-Torres, V.; Encinar, J.A.; Herranz-López, M.; Pérez-Sánchez, A.; Galiano, V.; Barrajón-Catalán, E.; Micol, V. An updated review on marine anticancer compounds: The use of virtual screening for the discovery of small-molecule cancer drugs. Molecules, 2017, 22(7), 1037.
[2]
Bhurgri, Y. Karachi cancer registry data-Implications for the national cancer control program of Pakistan. Asian Pac. J. Cancer Prev., 2004, 5(1), 77-82.
[3]
McCarthy, C.M.; Hamill, J.B.; Kim, H.M.; Qi, J.; Wilkins, E.; Pusic, A.L. Impact of bilateral prophylactic mastectomy and immediate reconstruction on health-related quality of life in women at high risk for breast carcinoma: Results of the mastectomy reconstruction outcomes consortium study. Ann. Surg. Oncol., 2017, 24(9), 2502-2508.
[4]
Fracasso, G.; Marzola, P.; Accardo, A. Liposomes derivatized with multimeric copies of KCCYSL peptide as targeting agents for HER-2-overexpressing tumor cells. Int. J. Nanomedicine, 2017, 12, 501.
[5]
Haldosén, L.A.; Zhao, C.; Dahlman-Wright, K. Estrogen receptor beta in breast cancer. Mol. Cell. Endocrinol., 2014, 382(1), 665-672.
[6]
Yam, C.; Mani, S.A.; Moulder, S.L. Targeting the molecular subtypes of triple negative breast cancer: Understanding the diversity to progress the field. Oncologist, 2017, 22(9), 1086-1093.
[7]
Denkert, C.; Liedtke, C.; Tutt, A.; von Minckwitz, G. Molecular alterations in triple-negative breast cancer - The road to new treatment strategies. Lancet, 2017, 389, 2430-2442.
[8]
Wahba, H.A.; El-Hadaad, H.A. Current approaches in treatment of triple-negative breast cancer. Cancer Biol. Med., 2015, 12(2), 106.
[9]
Abdelbadie, A.; Adam, E.A.; Abdelrahman, M. The effect of PT link and waterbath antigenic retrieval procedures on the expression of common receptors in breast cancer cases. Sudan J. Med. Sci., 2017, 12(1), 1-8.
[10]
Katzenellenbogen, B.S.; Zhao, Y.; Laws, M.J.; Guillen, V.S.; Ziegler, Y.; Min, J.; Oesterreich, S. Structurally novel antiestrogens elicit differential responses from constitutively active mutant estrogen receptors in breast cancer cells and tumors. Cancer Res., 2017, 77(20), 5602-5613.
[11]
Kurebayashi, J. Biological and clinical significance of HER2 overexpression in breast cancer. Breast Cancer, 2001, 8(1), 45-51.
[12]
Park, S.; Nedrow, J.R.; Josefsson, A.; Sgouros, G. Human HER2 overexpressing mouse breast cancer cell lines derived from MMTV. f. HuHER2 mice: Characterization and use in a model of metastatic breast cancer. Oncotarget, 2017, 8(40), 68071.
[13]
Das, J.R.; Fryar-Tita, E.B.; Zhou, Y.; Green, S.; Southerland, W.M.; Bowen, D. Sequence-dependent administration of 5-fluorouracil maintains methotrexate antineoplastic activity in human estrogen-negative breast cancer and protects against methotrexate cytotoxicity in human bone marrow. Anticancer Res., 2007, 27(6B), 3791-3799.
[14]
Ringhieri, P.; Mannucci, S.; Conti, G.; Nicolato, E.; Fracasso, G.; Marzola, P.; Accardo, A. Liposomes derivatized with multimeric copies of KCCYSL peptide as targeting agents for HER-2-overexpressing tumor cells. Int. J. Nanomedicine, 2017, 12, 501.
[15]
Kadow, J.F.; Meanwell, N.A.; Eastman, K.J.; Yeung, K.S.; DelMonte, A.J. Chemistry in the Pharmaceutical Industry. In: Handbook of Industrial Chemistry and Biotechnology; , 2017. Springer, pp. 531-579.
[16]
Kumar, D.; Sharma, P.; Singh, H.; Nepali, K.; Gupta, G.K.; Jain, S.K.; Ntie-Kang, F. The medicinal potential of synthetic and naturally occurring anticancer pyran scaffolds. Cell, 2017, 5, A498.
[17]
Potočňák, I.; Vranec, P.; Farkasová, V.; Sabolová, D.; Vataščinová, M.; Kudláčová, J.; Radojević, I.D.; Čomić, L.R.; Markovic, B.S.; Volarevic, V.; Arsenijevic, N. Low-dimensional compounds containing bioactive ligands. Part VI: Synthesis, structures, in vitro DNA binding, antimicrobial and anticancer properties of first row transition metal complexes with 5-chloro-quinolin-8-ol. J. Inorg. Biochem., 2016, 154, 67-77.
[18]
Kaushik, V.; Azad, N.; Yakisich, J.S.; Iyer, A.K.V. Antitumor effects of naturally occurring cardiac glycosides convallatoxin and peruvoside on human ER+ and triple-negative breast cancers. Cell Death Discov., 2017, 3, 17009.
[19]
Ramamoorthy, M.D.; Kumar, A.; Ayyau, M.; Dhiraviam, K.N. Reserpine induces apoptosis and cell cycle arrest in hormone independent prostate cancer cells through mitochondrial membrane potential failure. Anticancer. Agents Med. Chem., 2018, 18(9), 1313-1322.
[20]
Abdelfatah, S.A.; Efferth, T. Cytotoxicity of the indole alkaloid reserpine from Rauwolfia serpentina against drug-resistant tumor cells. Phytomedicine, 2015. 22(2015), 308-318
[21]
Nakamura, Y.; Yoshida, C.; Murakami, A.; Ohigashi, H.; Osawa, T.; Uchida, K. Zerumbone, a tropical ginger sesquiterpene, activates phase II drug metabolizing enzymes. FEBS Lett., 2004, 572(1-3), 245-250.
[22]
Yen, G.C.; Tsai, C.M.; Lu, C.C.; Weng, C.J. Recent progress in natural dietary non-phenolic bioactives on cancers metastasis. J. Food Drug Anal., 2018, 26(3), 940-964.
[23]
Eid, E.E.; Abdul, A.B.; Suliman, F.E.O.; Sukari, M.A.; Rasedee, A.; Fatah, S.S. Characterization of the inclusion complex of zerumbone with hydroxypropyl-β-cyclodextrin. Carbohydr. Polym., 2011, 83(4), 1707-1714.
[24]
Ma, J.W.; Hung, C.M.; Lin, Y.C.; Ho, C.T.; Kao, J.Y.; Way, T.D. Aloe-emodin inhibits HER-2 expression through the downregulation of Y-box binding protein-1 in HER-2-overexpressing human breast cancer cells. Oncotarget, 2016, 7(37), 58915.
[25]
Velaga, R.; Sugimoto, M. Future Paradigm of Breast Cancer Resistance and Treatment. In: Resistance to Targeted Therapies in Breast Cancer; , 2017. Springer, Cham, pp. 155-178.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 7
Year: 2019
Page: [738 - 742]
Pages: 5
DOI: 10.2174/1573406414666181106143912
Price: $65

Article Metrics

PDF: 26
HTML: 2