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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

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

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

Anticancer Drugs. 2018 Jan;29(1):50-60.

PMID: 29023248

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1402830754	Ceranib-2		1402830-75-4	Price

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