Combined Effects Of Bcl-x1 And Mcl-1 Antisense Oligonucleotides In Melanoma Drug Resistance.

Background and Objective: Melanoma is the most aggressive form of skin cancer and its prognosis is poor due to the development of drug resistance. Melanoma may have an intrinsic resistance to drugs, but acquired resistance may develop during chemotherapy , which may make the tumor cells not only resistant to the drugs originally used , but also cross-resistant to other drugs with different mechanisms of action. Thus, one of the main goals for melanoma treatment is to reverse chemoresistance of tumor cells.In recent years, the identification of apoptosis-related molecules , and their alteration in melanoma, have provided new insights into the molecular basis for melanoma chemoresistance. As most chemotherapeutic agents kill malignant cells by inducing apoptosis , and therefore, antiapoptosis can reduce the sensitivity of tumor cells to chemotherapeutic intervention. A number of studies have suggested that apoptosis and its regulation plays an important pathogenic role in the chemoresistance of human melanoma. Bcl-2-related proteins , key regulators of apoptosis, are the most frequently studied . The delicate balance between antiapoptotic and proapoptotic Bcl-2 family members determines whether the cell survives or undergoes apoptosis. In experimental models, it is found that mutations or altered expression of Bcl-2-related proteins can drastically alter drug sensitivity and are associated with multidrug resistance in human melanoma. There is growing evidence that reduction of Bcl-2 expression can induce apoptosis , enhance the chemosensitivity of cells and help to overcome chemoresistance in melanoma. Thus, Bcl-2 can be used for target selection in designing new anticancer agents.