Abstract
Second mitochondria-derived activator of caspases (SMAC) mimetics is a class of new anticancer agents. However, most cancers exhibit de novo or acquired resistance to SMAC mimetics, posting a problem for broad applications in clinic, and highlighting the necessity of exploring combinational strategies to circumvent SMAC mimetic-resistance. We here showed that Norcantharidin, a drug that is currently being used in cancer treatment, significantly enhanced SMAC mimetic Birinapant-mediated cell viability inhibition and robustly promoted apoptosis in established breast carcinoma cell lines, as well as in primary breast carcinoma cells. Mechanistically, we revealed that Norcantharidin effectively reduced the levels of two major protein isoforms of cellular FLICE-like inhibitor protein(c-FLIP), namely c-FLIP long (c-FLIPL) and c-FLIP short (c-FLIPS). Moreover, Norcantharidin markedly enhanced Birinapant-triggered caspase-8/caspase-3 cascade. Inhibition of caspase-8 activity by a synthetic peptide Z-IETD-FMK significantly attenuated cell death induction by the combination, suggesting that caspase-8 plays a critical role in the anticancer action. In conclusion, our study suggests that the combination of SMAC mimetics with Norcantharidin represents a novel strategy in breast cancer therapy and warrants further studies.
Highlights
Breast cancer is the most frequent type of cancer in women, and represents a major public health problem worldwide
Consistent with numerous previous reports showing that MDA-MB-231 cell line belonged to the most Second mitochondria-derived activator of caspases (SMAC) mimetic-sensitive cell lines [7,8,9, 16,17,18,19], we found that Birinapant potently inhibited the viability of MDA-MB-231 cell line, with an IC50 value of 15 nM after treatment for 48 h
We examined the effect of this SMAC mimetic on the expression of Inhibitor of apoptosis (IAP) in MDA-MB-231, MDA-MB-468 and MDA-MB-415 cell lines
Summary
Breast cancer is the most frequent type of cancer in women, and represents a major public health problem worldwide. X-linked IAP (XIAP), cellular IAP-1 (cIAP-1) and cellular IAP-2 (cIAP-2) are among the most intensively studied family IAP members. All these three IAPs have been documented as potent endogenous inhibitors against apoptosis signaling transduction. CIAP-1/2 play important roles in regulating tumor cell survival pathways such as Nuclear Factor kappaB (NF-κB) signaling [3, 4]. These IAP family members are significantly up-regulated in breast cancer tissues and cancer cells, and are negatively correlated with patient survival. As such, targeting IAPs is a promising therapeutic strategy for breast cancer [3]
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