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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Research Article

Effect of Calcitriol in Inhibiting the Cancer Cell Growth and Promoting Apoptosis in ErbB2-positive Breast Cancer Cells

Author(s): Nagaraj Balan Selvaraj, Akey Krishna Swaroop, Esakkimuthukumar Mariappan, Jawahar Natarajan, Prabha Thangavelu and Jubie Selvaraj*

Volume 23, Issue 18, 2023

Published on: 04 September, 2023

Page: [2056 - 2071] Pages: 16

DOI: 10.2174/1871520623666230822100006

Price: $65

Abstract

Background: Targeted therapies, specifically ErbB family tyrosine kinase inhibitors, have demonstrated potential for improving outcomes in patients with ErbB2-positive breast cancer. Despite their effectiveness, these therapies are associated with limitations, including high costs, side effects, drug resistance, lack of specificity, and toxicity. To overcome these challenges, drug repurposing has emerged as a promising strategy in breast cancer treatment.

Objective: The aim of this investigation was to assess the influence of calcitriol on breast cancer cell lines expressing ErbB2 and comparing its effects with the conventional treatment, neratinib.

Methods: We employed an MTT test to determine cell viability and utilized staining techniques to assess cell apoptosis. Flow cytometry was used to evaluate cell cycle arrest, while a scratch wound healing test was performed to examine cancer cell migration ability. Additionally, gene expression studies were conducted for calcitriol and neratinib to support our hypothesis regarding the ErbB2 gene.

Results: The repurposing of calcitriol demonstrated enhanced efficacy in suppressing cancer cell growth in ErbB2- positive breast cancer. Proportionally, calcitriol significantly reduced the viability of SK-BR-3 cells, similar to neratinib. Furthermore, calcitriol exhibited significant cytotoxicity against neratinib and substantially reduced breast cancer cell growth. These findings were corroborated by the wound healing assay, cell cycle arrest analysis, and gene expression studies, demonstrating comparable efficacy to the standard treatment, neratinib.

Conclusion: The findings from this investigation offer compelling proof that highlights the promising role of calcitriol as an adjuvant drug with antiproliferative and antitumoral effects in the management of ErbB2-positive breast carcinoma patients. Therefore, we recommend further evaluation of calcitriol in clinical settings, particularly for the treatment of ErbB2-positive breast cancer, as it shows promise as a valuable therapeutic option.

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[1]
Liu, D.; Bai, J.; Chen, Q.; Tan, R.; An, Z.; Xiao, J.; Qu, Y.; Xu, Y. Brain metastases: It takes two factors for a primary cancer to metastasize to brain. Front. Oncol., 2022, 12, 1003715.
[http://dx.doi.org/10.3389/fonc.2022.1003715] [PMID: 36248975]
[2]
Sigdel, I.; Gupta, N.; Faizee, F.; Khare, V.M.; Tiwari, A.K.; Tang, Y. Biomimetic microfluidic platforms for the assessment of breast cancer metastasis. Front. Bioeng. Biotechnol., 2021, 9, 633671.
[http://dx.doi.org/10.3389/fbioe.2021.633671] [PMID: 33777909]
[3]
Baylin, S.B.; Ohm, J.E. Epigenetic gene silencing in cancer: A mechanism for early oncogenic pathway addiction? Nat. Rev. Cancer, 2006, 6(2), 107-116.
[http://dx.doi.org/10.1038/nrc1799] [PMID: 16491070]
[4]
Breast Cancer Facts & Figures | American Cancer Society. Available From: https://www.cancer.org/research/cancer-facts-statistics/breast-cancer-facts-figures.html
[5]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[6]
Glass, A.G.; Lacey, J.V., Jr; Carreon, J.D.; Hoover, R.N. Breast cancer incidence, 1980-2006: Combined roles of menopausal hormone therapy, screening mammography, and estrogen receptor status. J. Natl. Cancer Inst., 2007, 99(15), 1152-1161.
[http://dx.doi.org/10.1093/jnci/djm059] [PMID: 17652280]
[7]
Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 - Ferlay. International Journal of Cancer - Wiley Online Library, 2023. Available From: https://onlinelibrary.wiley.com/doi/10.1002/ijc.29210 (Accessed on 2023 Mar 3).
[8]
Ghoncheh, M.; Pournamdar, Z.; Salehiniya, H. Incidence and mortality and epidemiology of breast cancer in the world. Asian Pac. J. Cancer Prev., 2016, 17(sup3), 43-46.
[http://dx.doi.org/10.7314/APJCP.2016.17.S3.43] [PMID: 27165206]
[9]
Jemal, A.; Center, M.M.; DeSantis, C.; Ward, E.M. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol. Biomarkers Prev., 2010, 19(8), 1893-1907.
[http://dx.doi.org/10.1158/1055-9965.EPI-10-0437] [PMID: 20647400]
[10]
Breast cancer. Available From: https://www.who.int/news-room/fact-sheets/detail/breast-cancer (Accessed on 2022 Feb 27)
[11]
de Araújo, R.A.; da Luz, F.A.C.; da Costa, M. E.; Nascimento, C.P.; de Andrade, M, L.; Delfino, P.F.R.; Antonioli, R.M.; Araújo, B.J.; da Silva, A.C.A.L.; Dos Reis Monteiro, M.L.G.; Neto, M.B.; Silva, M.J.B. Epidermal growth factor receptor (EGFR) expression in the serum of patients with triple-negative breast carcinoma: Prognostic value of this biomarker. Ecancermedicalscience, 2022, 16, 1431.
[PMID: 36158981]
[12]
Al-Abdallah, A.; Jahanbani, I.; Ali, R.H.; Al-Brahim, N.; Prasanth, J.; Al-Shammary, B.; Al-Bader, M. A new paradigm for epidermal growth factor receptor expression exists in PTC and NIFTP regulated by microRNAs. Front. Oncol., 2023, 13, 1080008.
[http://dx.doi.org/10.3389/fonc.2023.1080008] [PMID: 37114127]
[13]
Vu, T.; Claret, F.X. Trastuzumab: Updated mechanisms of action and resistance in breast cancer. Front. Oncol., 2012, 2, 62. https://www.frontiersin.org/articles/10.3389/fonc.2012.00062
[http://dx.doi.org/10.3389/fonc.2012.00062] [PMID: 22720269]
[14]
Owens, M.A.; Horten, B.C.; Da Silva, M.M. HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin. Breast Cancer, 2004, 5(1), 63-69.
[http://dx.doi.org/10.3816/CBC.2004.n.011] [PMID: 15140287]
[15]
Peiffer, D.S.; Zhao, F.; Chen, N.; Hahn, O.M.; Nanda, R.; Olopade, O.I.; Huo, D.; Howard, F.M. Clinicopathologic characteristics and prognosis of ERBB2-Low breast cancer among patients in the national cancer database. JAMA Oncol., 2023, 9(4), 500-510.
[http://dx.doi.org/10.1001/jamaoncol.2022.7476] [PMID: 36821125]
[16]
Beasley, M.; Daniel, B. Advancing the care of women with HER2-positive metastatic breast cancer. J. Adv. Pract. Oncol., 2023, 14(3), 248-251.
[http://dx.doi.org/10.6004/jadpro.2023.14.3.13] [PMID: 37197725]
[17]
Ménard, S.; Balsari, A.; Casalini, P.; Tagliabue, E.; Campiglio, M.; Bufalino, R.; Cascinelli, N. HER-2-positive breast carcinomas as a particular subset with peculiar clinical behaviors. Clin. Cancer Res., 2002, 8(2), 520-525.
[PMID: 11839672]
[18]
Grupka, N.L.; Lear-Kaul, K.C.; Kleinschmidt-DeMasters, B.K.; Singh, M. Epidermal growth factor receptor status in breast cancer metastases to the central nervous system. Comparison with HER-2/neu status. Arch. Pathol. Lab. Med., 2004, 128(9), 974-979.
[http://dx.doi.org/10.5858/2004-128-974-EGFRSI] [PMID: 15335267]
[19]
Gaedcke, J.; Traub, F.; Milde, S.; Wilkens, L.; Stan, A.; Ostertag, H.; Christgen, M.; von Wasielewski, R.; Kreipe, H.H. Predominance of the basal type and HER-2/neu type in brain metastasis from breast cancer. Mod. Pathol., 2007, 20(8), 864-870.
[http://dx.doi.org/10.1038/modpathol.3800830] [PMID: 17541441]
[20]
Roy, V.; Perez, E.A. Beyond trastuzumab: Small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer. Oncologist, 2009, 14(11), 1061-1069.
[http://dx.doi.org/10.1634/theoncologist.2009-0142] [PMID: 19887469]
[21]
Shao, M.M.; Liu, J.; Vong, J.S.; Niu, Y.; Germin, B.; Tang, P. A subset of breast cancer predisposes to brain metastasis. Med. Mol. Morphol., 2011, 44(1), 15-20.
[22]
Yarden, Y.; Sliwkowski, M.X. Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol., 2001, 2(2), 127-137.
[http://dx.doi.org/10.1038/35052073] [PMID: 11252954]
[23]
Lim, E.; Lin, N.U. Updates on the management of breast cancer brain metastases. Oncology, 2014, 28(7), 572-578.
[PMID: 25144276]
[24]
Witton, C.J.; Reeves, J.R.; Going, J.J.; Cooke, T.G.; Bartlett, J.M.S. Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer. J. Pathol., 2003, 200(3), 290-297.
[http://dx.doi.org/10.1002/path.1370] [PMID: 12845624]
[25]
Tsutsui, S.; Ohno, S.; Murakami, S.; Hachitanda, Y.; Oda, S. Prognostic value of epidermal growth factor receptor (EGFR) and its relationship to the estrogen receptor status in 1029 patients with breast cancer. Breast Cancer Res. Treat., 2002, 71(1), 67-75.
[http://dx.doi.org/10.1023/A:1013397232011] [PMID: 11859875]
[26]
Pu, J.; Guo, H.; Yu, R.; Ou, Q. B, H.; Wu, X.; Tang, S.; Chang, Q. Pan-cancer molecular analysis ofEGFR large fragment deletion in the Asian population. Cancer Med., 2023, 12(7), 8083-8088.
[http://dx.doi.org/10.1002/cam4.5603] [PMID: 36622089]
[27]
Cobleigh, M.A.; Vogel, C.L.; Tripathy, D.; Robert, N.J.; Scholl, S.; Fehrenbacher, L.; Wolter, J.M.; Paton, V.; Shak, S.; Lieberman, G.; Slamon, D.J. Multinational study of the efficacy and safety of humanized Anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. Clin. Oncol., 2023, 41(8), 1501-1510.
[http://dx.doi.org/10.1200/JCO.22.02510] [PMID: 36881998]
[28]
Maennling, A.E.; Tur, M.K.; Niebert, M.; Klockenbring, T.; Zeppernick, F.; Gattenlöhner, S.; Meinhold-Heerlein, I.; Hussain, A.F. Molecular targeting therapy against EGFR family in breast cancer: Progress and future potentials. Cancers, 2019, 11(12), 1826.
[http://dx.doi.org/10.3390/cancers11121826] [PMID: 31756933]
[29]
Skolariki, A.; D’Costa, J.; Little, M.; Lord, S. Role of PI3K/Akt/mTOR pathway in mediating endocrine resistance: Concept to clinic. Explor. Target Antitumor Ther., 2022, 3(2), 172-199.
[http://dx.doi.org/10.37349/etat.2022.00078] [PMID: 36046843]
[30]
Sartor, C.I.; Zhou, H.; Kozlowska, E.; Guttridge, K.; Kawata, E.; Caskey, L.; Harrelson, J.; Hynes, N.; Ethier, S.; Calvo, B.; Earp, H.S., III Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells. Mol. Cell. Biol., 2001, 21(13), 4265-4275.
[http://dx.doi.org/10.1128/MCB.21.13.4265-4275.2001] [PMID: 11390655]
[31]
Atalay, G.; Cardoso, F.; Awada, A.; Piccart, M.J. Novel therapeutic strategies targeting the epidermal growth factor receptor (EGFR) family and its downstream effectors in breast cancer. Ann. Oncol., 2003, 14(9), 1346-1363.
[http://dx.doi.org/10.1093/annonc/mdg365] [PMID: 12954573]
[32]
Moasser, M.M. The oncogene HER2: Its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene, 2007, 26(45), 6469-6487.
[http://dx.doi.org/10.1038/sj.onc.1210477] [PMID: 17471238]
[33]
Issekutz, A.C.; Quinn, P.J.; Lang, B.; Ramsey, S.; Huber, A.M.; Rowter, D.; Karkada, M.; Issekutz, T.B. Coexpression of chemokine receptors CCR5, CXCR3, and CCR4 and ligands for P- and E-selectin on T lymphocytes of patients with juvenile idiopathic arthritis. Arthritis Rheum., 2011, 63(11), 3467-3476.
[http://dx.doi.org/10.1002/art.30521] [PMID: 21739422]
[34]
Fornasari, B.E.; El Soury, M.; De Marchis, S.; Perroteau, I.; Geuna, S.; Gambarotta, G. Neuregulin1 alpha activates migration of neuronal progenitors expressing ErbB4. Mol. Cell. Neurosci., 2016, 77, 87-94.
[http://dx.doi.org/10.1016/j.mcn.2016.10.008] [PMID: 27989735]
[35]
Sirkisoon, S.R.; Carpenter, R.L.; Rimkus, T.; Miller, L.; Metheny-Barlow, L.; Lo, H.W. EGFR and HER2 signaling in breast cancer brain metastasis. Front. Biosci., 2016, 8(2), 245-263.
[PMID: 26709660]
[36]
Hsu, J.L.; Hung, M.C. The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev., 2016, 35(4), 575-588.
[http://dx.doi.org/10.1007/s10555-016-9649-6] [PMID: 27913999]
[37]
B S. N.; P K, K.N.; Akey, K.S.; Sankaran, S.; Raman, R.K.; Natarajan, J.; Selvaraj, J. Vitamin D analog calcitriol for breast cancer therapy; an integrated drug discovery approach. J. Biomol. Struct. Dyn., 2023, 1-27.
[http://dx.doi.org/10.1080/07391102.2023.2199866] [PMID: 37054526]
[38]
Rainville, C.; Khan, Y.; Tisman, G. Triple negative breast cancer patients presenting with low serum vitamin D levels: A case series. Cases J., 2009, 2(1), 8390.
[http://dx.doi.org/10.4076/1757-1626-2-8390] [PMID: 19830074]
[39]
Association between low levels of 1,25-dihydroxyvitamin D and breast cancer risk - PubMed. Available From: https://pubmed.ncbi.nlm.nih.gov/10512563/ (Accessed on 2023 Apr 17)
[40]
Christakos, S.; Dhawan, P.; Verstuyf, A.; Verlinden, L.; Carmeliet, G.; Vitamin, D. Metabolism, molecular mechanism of action, and pleiotropic effects. Physiol. Rev., 2016, 96(1), 365-408.
[http://dx.doi.org/10.1152/physrev.00014.2015] [PMID: 26681795]
[41]
Swaroop, A.K.; Sunil, K.P.; Vasanth, P.; Jeyaprakash, M.R.; Praharsh, K.M.R.; Jawahar, N.; Jubie, S. Design and synthesis of novel quercetin metal complexes as IL-6 inhibitors for anti-inflammatory effect in SARS-CoV-2. Indian J. Biochem. Biophys., 2020, 59, 824-836.
[42]
Jubie, S.; Jameera, B.A.; Nanjan, M.J.; Justin, A.; Ashish, W.; Jawahar, N. Coumarin-fatty acid conjugates as potential ER-/AKT-1 antagonists for ER positive breast cancer. Anticancer. Agents Med. Chem., 2020, 20, 437-449.
[43]
Esakkimuthukumar, M.; Swaroop, A.K.; Sunil, K. P.; Rajesh Kumar, R.; Praveen, T. K.; Ravi, N, M.; Jubie, S. A novel family of small molecule HIF-1 alpha stabilizers for the treatment of diabetic wounds; an integrated in silico, in vitro, and in vivo strategy. RSC Advances, 2022, 12, 31293.
[44]
Praharsh Kumar, M. Bala Sai Soujith Nidamanuri, Swaroop, A.K.; Janani, S.K.; Anjali, P.B.; Jubie, S.; Rajeshkumar, R.; Shivakumar, H.N.; Vivek Reddy, M.; Jawahar, N. Fabrication and in vitro evaluation of silk fibroin-folic acid decorated paclitaxel and hydroxyurea nanostructured lipid carriers for targeting ovarian cancer cells: A double sword approach. J. Drug Deliv. Sci. Technol., 2023, 81, 104270.
[45]
Rao, X.; Huang, X.; Zhou, Z.; Lin, X. An improvement of the 2^(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostat. Bioinforma. Biomath., 2013, 3(3), 71-85.
[PMID: 25558171]
[46]
Deepthi, R.; Jubie, S.; Vasanth, R. P.; Vyshnavi, T.; Chandrasekar, M.J.N. Down regulation of NT5C3 gene expressions by elastin-like polypeptide gemcitabine conjugate for ovarian cancer therapy. J. Drug Deliv. Sci. Technol., 2022, 76, 103821.
[47]
Singh, J.C.; Jhaveri, K.; Esteva, F.J. HER2-positive advanced breast cancer: Optimizing patient outcomes and opportunities for drug development. Br. J. Cancer, 2014, 111(10), 1888-1898.
[http://dx.doi.org/10.1038/bjc.2014.388] [PMID: 25025958]
[48]
Saura, C.; Oliveira, M.; Feng, Y.H.; Dai, M.S.; Chen, S.W.; Hurvitz, S.A.; Kim, S.B.; Moy, B.; Delaloge, S.; Gradishar, W.; Masuda, N.; Palacova, M.; Trudeau, M.E.; Mattson, J.; Yap, Y.S.; Hou, M.F.; De Laurentiis, M.; Yeh, Y.M.; Chang, H.T.; Yau, T.; Wildiers, H.; Haley, B.; Fagnani, D.; Lu, Y.S.; Crown, J.; Lin, J.; Takahashi, M.; Takano, T.; Yamaguchi, M.; Fujii, T.; Yao, B.; Bebchuk, J.; Keyvanjah, K.; Bryce, R.; Brufsky, A. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Phase III NALA trial. J. Clin. Oncol., 2020, 38(27), 3138-3149.
[http://dx.doi.org/10.1200/JCO.20.00147] [PMID: 32678716]
[49]
Collins, D.M.; Conlon, N.T.; Kannan, S.; Verma, C.S.; Eli, L.D.; Lalani, A.S.; Crown, J. Preclinical characteristics of the irreversible pan-HER kinase inhibitor neratinib compared with lapatinib: Implications for the treatment of HER2-positive and HER2-mutated breast cancer. Cancers, 2019, 11(6), 737.
[http://dx.doi.org/10.3390/cancers11060737] [PMID: 31141894]
[50]
Ma, Y.; Trump, D.L.; Johnson, C.S. Vitamin D in combination cancer treatment. J. Cancer, 2010, 1, 101-107.
[http://dx.doi.org/10.7150/jca.1.101] [PMID: 20842231]
[51]
Trump, D.L.; Deeb, K.K.; Johnson, C.S.; Vitamin, D. Considerations in the continued development as an agent for cancer prevention and therapy. Cancer J., 2010, 16(1), 1-9.
[http://dx.doi.org/10.1097/PPO.0b013e3181c51ee6] [PMID: 20164683]
[52]
Segovia-Mendoza, M.; Díaz, L.; Prado-Garcia, H.; Reginato, M.J.; Larrea, F.; García-Becerra, R. The addition of calcitriol or its synthetic analog EB1089 to lapatinib and neratinib treatment inhibits cell growth and promotes apoptosis in breast cancer cells. Am. J. Cancer Res., 2017, 7(7), 1486-1500.
[PMID: 28744399]

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