Anti-MCL1 monoclonal antibody, clone 3F22

Resistance acquired toward anti-cancer agents is a significant drawback in breast cancer therapy. A key factor contributing to drug resistance is apoptosis suppression associated with the upregulation of anti-apoptotic Bcl-2 family proteins. Specifically, the anti-apoptotic Mcl-1 protein has been shown to play a significant role in drug resistance, making it an important therapeutic target. The present study aimed at determining the antiproliferative activity of 3-chloroplumbagin (ChPL), a naphthoquinone derived from a Dionaea sp., toward breast cancer cells and examining the involvement of Mcl-1 inhibition in ChPL-induced cell death. The results showed that ChPL inhibited breast cancer cell proliferation and induced apoptosis through the intrinsic pathway through down-regulation of antiapoptotic Bcl-2 family proteins. The induction of apoptosis by ChPL was found to be mediated through MAP kinase signaling inhibition. ChPL inhibited the phosphorylation of MEK and ERK proteins in breast cancer cells, and increased apoptosis induction in cells with reduced ERK expression. Furthermore, ERK silencing decreased the expression of Mcl-1 in ChPL-treated cells. The results of this research indicate that ChPL induces apoptosis in breast cancer cells through MAPK-mediated Mcl-1 inhibition, suggesting further research into its potential in breast cancer treatment.

Patients with urothelial carcinoma frequently fail to respond to first-line chemotherapy using cisplatin and gemcitabine due to development of resistant tumor cells. The aim of the present study was to investigate whether an alternative treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that induces tumor cell death via the extrinsic apoptotic pathway may be effective against chemotherapy-resistant urothelial cancer cell lines. The viability of the urothelial cancer cell line RT112 and its chemotherapy-adapted sublines was investigated by MTT assay. The expression of anti-apoptotic proteins was determined by western blotting and the individual roles of cellular inhibitor of apoptosis protein (cIAP)1, cIAP2, x-linked inhibitor of apoptosis protein (XIAP) and induced myeloid leukemia cell differentiation protein (Mcl-1) were investigated by siRNA-mediated depletion. In particular, the bladder cancer sublines that were resistant to gemcitabine and cisplatin were cross-resistant to TRAIL. Resistant cells displayed upregulation of anti-apoptotic molecules compared with the parental cell line. Treatment with the second mitochondrial activator of caspases (SMAC) mimetic LCL-161 that antagonizes cIAP1, cIAP2 and XIAP resensitized chemoresistant cells to TRAIL. The resensitization of tumor cells to TRAIL was confirmed by depletion of antiapoptotic proteins with siRNA. Collectively, the findings of the present study demonstrated that SMAC mimetic LCL-161 increased the sensitivity of the parental cell line RT112 and chemotherapy-resistant sublines to TRAIL, suggesting that inhibiting anti-apoptotic molecules renders TRAIL therapy highly effective for chemotherapy-sensitive and -resistant urothelial cancer cells.