Secondary Logo

Journal Logo

Institutional members access full text with Ovid®

Anticancer effect of acid ceramidase inhibitor ceranib-2 in human breast cancer cell lines MCF-7, MDA MB-231 by the activation of SAPK/JNK, p38 MAPK apoptotic pathways, inhibition of the Akt pathway, downregulation of ERα

Vethakanraj, Helen, S.; Sesurajan, Binny, P.; Padmanaban, Vishnu, P.; Jayaprakasam, Madhumathi; Murali, Suganthi; Sekar, Ashok, K.

doi: 10.1097/CAD.0000000000000566
PRECLINICAL REPORTS
Buy

Acid ceramidase is the key enzyme of the ceramide metabolic pathway, which plays a vital role in regulating ceramide – sphingosine-1-phosphate rheostat. Ceramide acts as a proapoptotic molecule, but its metabolite sphingosine-1-phosphate, in contrast, signals for cell proliferation, cell survival, and angiogenesis. Acid ceramidase is highly upregulated in breast tumors and treatment with an acid ceramidase inhibitor, ceranib-2, significantly induced apoptosis in human breast cancer cell lines. However, the mechanisms underlying the induction of apoptosis remain ambiguous to date. Hence, in the present study, we have explored ceranib-2-mediated apoptotic signaling pathways in human breast cancer cell lines. MCF-7 and MDA MB-231 cells were treated with IC50 doses of ceranib-2 and tamoxifen. Nuclear changes showed the apoptotic effect of ceranib-2 in both the cell lines. Loss in the mitochondrial membrane potential was observed only in ceranib-2-treated MCF-7 cells. Ceranib-2 activated intrinsic and extrinsic apoptotic pathways in MCF-7 cells, but only the extrinsic apoptotic pathway was activated in MDA MB-231 cells. Further, ceranib-2 induced apoptosis by activating SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal kinase), p38 MAPK (mitogen-activated protein kinase) apoptotic pathways and by inhibiting the Akt (antiapoptotic) pathway in both the cell lines. Most importantly, ERα (estrogen receptor-α) expression was highly downregulated after ceranib-2 treatment and a docking study predicted the highest binding affinity of ceranib-2 than tamoxifen with ERα in MCF-7 cells. Hence, ceranib-2 may have potential as a chemotherapeutic drug of breast cancer.

Centre for Biotechnology, Anna University, Chennai, India

Correspondence to Ashok K. Sekar, PhD, Centre for Biotechnology, Anna University, A.C. Tech Campus, Sardar Patel Road, Chennai 600025, Tamilnadu, India Tel: +91 962 967 0607; fax: +91 44 223 58388; e-mail: sekarashok@gmail.com

Received July 4, 2017

Accepted September 4, 2017

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.