Speaker: Dr. Chengguo Xing, Department of Medicinal Chemistry, University of Minnesota

Abstract:

Drug resistance is a major challenge to the success of cancer chemotherapy. One mechanism by which tumor acquires resistance is through elevation of the level of anti-apoptotic Bcl-2 family proteins. Antagonizing these apoptotic inhibitory proteins is therefore a promising approach to overcoming drug resistance in cancer therapy. sHA 14-1 - a stable analog of HA 14-1 was recently synthesized in this laboratory as a putative antagonist against anti-apoptotic Bcl-2 family proteins, which effectively induces apoptosis in tumor cells.

In the current presentation, we demonstrated that sHA 14-1 can selectively target various drug-resistant leukemia cells, which have elevated levels of anti-apoptotic Bcl-2 proteins, such as Bcl-2, Bcl-XL, and Mcl-1. As a putative Bcl-2 antagonist, sHA 14-1 also synergized the activities of chemotherapeutic agents with distinct mechanisms of action. Moreover, sHA 14-1 revealed selective toxicity against human leukemic cells while exhibiting minimal toxicity toward normal human lymphoial cells. Mechanistically, sHA 14-1 induced endoplasmic reticulum (ER) calcium release in vitro within seconds upon treatment, which was demonstrated to be critical for the cytoxicity of sHA 14-1. ER stress in vitro was detected within one hour after sHA 14-1 treatment while loss of mitochondrial membrane potential was not detected until 6 hours after sHA 14-1 treatment, indicating that ER is the upper stream organelle compared to mitochondria for sHA 14-1 to induce cell death. We also demonstrated that sHA 14-1 induced ER calcium release through directly interacting with cellular targets on ER, instead of indirect signal transduction.

Furthermore, the drug-resistant leukemic cells had elevated levels of ER calcium, and sHA 14-1 treatment at the same concentrations resulted in more ER calcium release from drug-resistant cells than that from parent leukemic cells. The differential potency of sHA 14-1 to induce [Ca2+]ER release explained the selective toxicity of sHA 14-1 against drug resistant cancer.

Given the fact that ER-localized anti-apoptotic Bcl-2 proteins induce drug resistance through regulating calcium homeostasis, we propose that sHA 14-1 antagonizes ER-specific anti-apoptotic Bcl-2 proteins to induce [Ca2+]ER release, which serves as the up-stream signals for its anticancer activity, independent of mitochondrial apoptotic pathway.