Identification of endoplasmic reticulum stress-inducing agents by antagonizing autophagy: a new potential strategy for identification of anti-cancer therapeutics in B-cell malignancies

Abstract

The endoplasmic reticulum (ER) plays a vital function in multiple cellular processes. There is a growing interest in developing therapeutic agents that can target the ER in cancer cells, inducing a stress response that leads to cell death. However, ER stress-inducing agents can also induce autophagy, a survival strategy of cancer cells. Therefore, by inhibiting autophagy we can increase the efficacy of the ER stress-inducing agents. Nelfinavir, a human immunodeficiency virus (HIV) protease inhibitor with anti-cancer properties, can induce ER stress. Nelfinavir's effects on chronic lymphocytic leukemia (CLL) are yet to be elucidated. Herein we demonstrate that nelfinavir induces ER morphological changes and stress response, along with an autophagic protective strategy. Our data reveal that chloroquine, an autophagy inhibitor, significantly increases nelfinavir cytotoxicity. These results identify a novel strategy potentially effective in CLL treatment, by repositioning two well-known drugs as a combinatorial therapy with anti-cancer properties.

Keywords::

• Nelfinavir
• autophagy
• ER stress
• drug screening
• chronic lymphocytic leukemia

Potential conflict of interest

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This work was supported by the Leukemia and Lymphoma Society Specialized Center of Research, D. Warren Brown Foundation, National Cancer Institute K12CA133250 and a NIH NRSA T32 Oncology Training Grant. All immunofluorescence imaging was performed at the Campus Microscopy and Imaging Facility, The Ohio State University, Columbus, Ohio.