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Ref Type Journal Article
PMID (26803057)
Authors Jing Z, Sui X, Yao J, Xie J, Jiang L, Zhou Y, Pan H, Han W
Title SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIγ/AKT-mediated pathway.
Journal Cancer letters
Vol 372
Issue 2
Date 2016 Mar 28
Abstract Text Store-operated Ca(2+) entry (SOCE) inhibitors are emerging as an attractive new generation of anti-cancer drugs. Here, we report that SKF-96365, an SOCE inhibitor, exhibits potent anti-neoplastic activity by inducing cell-cycle arrest and apoptosis in colorectal cancer cells. In the meantime, SKF-96365 also induces cytoprotective autophagy to delay apoptosis by preventing the release of cytochrome c (cyt c) from the mitochondria into the cytoplasm. Mechanistically, SKF-96365 treatment inhibited the calcium/calmodulin-dependent protein kinase IIγ (CaMKIIγ)/AKT signaling cascade in vitro and in vivo. Overexpression of CaMKIIγ or AKT abolished the effects of SKF-96365 on cancer cells, suggesting a critical role of the CaMKIIγ/AKT signaling pathway in SFK-96365-induced biological effects. Moreover, Hydroxychloroquine (HCQ), an FDA-approved drug used to inhibit autophagy, could significantly augment the anti-cancer effect of SFK-96365 in a mouse xenograft model. To our best knowledge, this is the first report to demonstrate that calcium/CaMKIIγ/AKT signaling can regulate apoptosis and autophagy simultaneously in cancer cells, and the combination of the SOCE inhibitor SKF-96365 with autophagy inhibitors represents a promising strategy for treating patients with colorectal cancer.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
SKF-96365 SKF 96365|SKF96365 SKF-96365 is a non-specific inhibitor of store-operated calcium entry, leading to cell-cycle arrest and suppression of tumor cell growth (PMID: 23383239, PMID: 20590636, PMID: 26803057).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colorectal cancer not applicable SKF-96365 Preclinical - Cell line xenograft Actionable In a preclinical study, SKF-96365 treatment inhibited the calcium/calmodulin dependent protein kinase signaling leading to decreased proliferation and increased apoptosis of human colorectal cancer cells in culture and had moderate anti-cancer activity in cell line xenograft models (PMID: 26803057). 26803057