**5. Therapeutic targeting of defective apoptosis in cancer**

Apoptosis plays a pivotal role in cancer pathogenesis. Therefore, understanding the molecular basis of defective apoptosis has garnered tremendous attention from medical researchers. Novel therapeutic agents and treatment modalities to modulate disease pathogenesis are under trials in both preclinical and clinical settings. An important strategy to modulate cancer pathogenesis involves the use of small molecule inhibitors (SMIs) that target specific components in apoptotic cascades.

### **5.1 Targeting anti-apoptotic Bcl-2 family members**

Bcl-2 is over expressed in many types of tumors and imparts therapeutic intractability to such tumors. A highly selective inhibitor of Bcl-2 is Venetoclax. This drug has been approved for routine clinical practice and is currently in use for the treatment of ALL (acute lymphocytic leukemia), CLL (chronic lymphocytic leukemia), and multiple myeloma T-cell prolymphocytic leukemia. Venetoclax is a Bcl2-selective BH3-mimetic. BH3-mimetics represents a class of anticancer drug that mimic the functions of BH3-only proteins. These mimetics bind to prosurvival proteins like Bcl-2 and inhibit their ability to bind Bax or Bak [38]. Thus, when Bcl-2 overexpressing cancer cells are treated with venetoclax *in vitro*, the cancer cells undergo apoptosis. Venetoclax is often used alone or in combination with other drugs such as rituximab, ibrutinib, azacitidine/decitabine, and bortezomib/ dexamethasone against various hematological malignancies. Bcl-2 family members over expression are affiliated with aggressive cancer and chemo resistive [39]. These credentials make these proteins as highly encouraging therapeutic targets to develop pharmacological anticancer drugs. Bcl-2 family members inhibition by small interfering RNAs (siRNAs) may also induce apoptosis and can reduce tumor growth [40]. For example, Mcl-1 down regulation by siRNA induced significant

apoptosis in leukemia cells. Many different microRNAs have been associated that regulate Bcl-2 expression such as miR-195, miR-24-2, and miR-365-2 act as negative regulators of Bcl-2 family, which shows the therapeutic potential of these miRNAs [16, 41].
