Recent advances in the development of anticancer agents targeting cell death inhibitors in the Bcl-2 protein family

The antiapoptotic member of the Bcl-2 family Mcl-1 is a CTL target in cancer patients

“…2 Elevated levels of Mcl-1 have been reported for a number of human cancers including prostate cancers, 3 pancreatic cancers, melanoma, breast cancers, ovarian cancer patients, and cervical cancer, as well as Bcell chronic lymphocytic leukemia (B-CLL) and in AML and ALL upon relapse. [4][5][6] In B-CLL patients, higher levels of Mcl-1 are strongly correlated with failure to achieve complete remission after single-agent therapy. In multiple myeloma, Mcl-1 plays an important role in the survival of malignant cells.…”

Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells

“…More recently, considerable attention has been drawn to small organic molecules or short peptides that antagonize or mimic the function of apoptosis-regulating gene products. Promising examples of this approach are the inhibitors of Bcl-2 and Bcl-x L [9][10][11] and the short peptides that substitute for the mitochondrial proapoptotic Smac protein. 12 Finally, the successful use of small interfering RNAs (siRNAs) to downregulate gene expression in several model systems [13][14][15][16][17][18] has led to many attempts to explore this methodology in potentially therapeutic settings.…”

Mcl-1 and anticancer vaccination: identification of an HLA-A2-restricted epitope

“…3 In a prospective study in AML patients, low expression of CXCR4 on the membrane of blast cells by flow cytometry associated with a longer relapse-free and overall survival, and CXCR4 expression level maintained an independent prognostic value together with unfavorable cytogenetics in a multivariate analysis. 4 The role of CXCR4 in circulation of leukemic blasts and the development of extramedullary disease has been explored also in childhood acute lymphoblastic leukemia. A significant correlation between high-membrane level of CXCR4 and the enlargement of spleen or liver was found, independently of the count of lymphoblasts in the circulation.…”

“…Mcl-1 plays an important role in cancer as it has been directly linked to the resistance to conventional forms of therapies and poor prognosis. 4 Recently, we demonstrated that cancer patients of different origin host spontaneous T-cell responses specifically against Mcl-1-derived peptides presented in the context of the HLA-A1 and -A3 antigen. [5][6][7] However, the Mcl-1-based clinical vaccination trials await the identification of an HLA-A2-restricted epitope from Mcl-1 as HLA-A2 is the most frequent HLA-allele in the Caucasian population expressed by 50%.…”