Sonia Das - sHA14-1, a stable and  ROS-free antagonist against anti-apoptotic Bcl-2 proteins, bypasses drug resistances and synergizes cancer therapies in human  leukaemia cell

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      Publication Details (including relevant citation   information):

      Cancer letters 259 (2008), 2, 198-208

      doi:10.1016/j.canlet.2007.10.012

      Abstract:

      HA 14-1, a small-molecule antagonist against anti-apoptotic   Bcl-2  proteins, was demonstrated to induce selective   cytotoxicity toward  malignant cells and to overcome drug   resistance. Due to its poor  stability and the reactive   oxygen species (ROS) generated by its  decomposition,   chemical modification of HA 14-1 is needed for its future    development. We have synthesized a stabilized analog of HA 14-1 –   sHA  14-1, which did not induce the formation of ROS. As   expected from a  putative antagonist against anti-apoptotic   Bcl-2 proteins like HA 14-1,  sHA 14-1 disrupted the binding   interaction of a Bak BH3 peptide with  Bcl-2 or Bcl-XL   protein, inhibited the  growth of tumor cells through the   induction of apoptosis, and  circumvented the drug   resistance induced by the over-expression of  anti-apoptotic   Bcl-2 and Bcl-XL  proteins. Interestingly, the impairment of   extrinsic apoptotic pathway  induced moderate resistance to   sHA 14-1. The moderate resistance  suggested that sHA 14-1   generated part of its apoptotic stress through  the   intrinsic pathway, possibly through its antagonism against    anti-apoptotic Bcl-2 proteins. The resistance indicated that sHA   14-1  generated apoptotic stress through the extrinsic   apoptotic pathway as  well. The ability of sHA 14-1 to   induce apoptotic stress through both  pathways was further   supported by the synergism of sHA 14-1 towards the    cytotoxicities of Fas ligand and dexamethasone in Jurkat cells.   Taken  together, these findings suggest that sHA 14-1 may   represent a promising  candidate for the treatment of   drug-resistant cancers either as a  monotherapy or in   combination with current cancer therapies.

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