Abstract
Pancreatic cancer (PC) has a complex etiology and displays a wide range of cellular escape pathways that allow it to resist different treatment modalities. Crucial signaling molecules that function downstream of the survival pathways, particularly at points where several of these pathways crosstalk, provide valuable targets for the development of novel anti-cancer drugs. Bcl-2 family member proteins are anti-apoptotic molecules that are known to be overexpressed in most cancers including PC. The anti-apoptotic machinery has been linked to the observed resistance developed to chemotherapy and radiation and therefore is important from the targeted drug development point of view. Over the past ten years, our group has extensively studied a series of small molecule inhibitors of Bcl-2 against PC and provide solid preclinical platform for testing such novel drugs in the clinic. This review examines the efficacy, potency, and function of several small molecule inhibitor drugs targeted to the Bcl-2 family of proteins and their preclinical progress against PC. This article further focuses on compounds that have been studied the most and also discusses the anti-cancer potential of newer class of Bcl-2 drugs.
Highlights
Pancreatic cancer (PC) is a therapy refractory and deadly disease with a an annual mortality of ~35,000 in the UnitedStates [1]
We have previously shown that TW-37 has high affinity for B cell lymphoma 2 (Bcl-2) in addition to Bcl-xL and targets Mcl-1 unlike other SMIs
Our findings provided evidence that TW-37 could act as a small-molecule Bcl-2 inhibitor on wellcharacterized PC cells in culture as well as when grown as tumor in a xenograft model
Summary
PC is a therapy refractory and deadly disease with a an annual mortality of ~35,000 in the United. With respect to the multitude of anti-apoptotic pathways, a great number of molecular targets might be of high potential in novel therapy strategies, which is the theme of this issue Even though these early studies encouraged an application in a clinical setting, most of the trials have been rather disappointing to date. Overexpression of BCL-2 and associated anti-apoptotic proteins Bcl-xL, Mcl-1, and BCL-W occurs in substantial subsets of common cancer types that include pancreatic, ovarian, lymphoma , multiple myeloma, lung adenocarcinoma, prostate adenocarcinoma, etc [27,28] These Bcl-2 proteins can essentially make cancer cells resistant to a variety of chemotherapeutic agents and these proteins are currently important targets for the development of new anti-cancer agents [29]
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