Autophagy Inhibition for Chemosensitization and Radiosensitization in Cancer: Do the Preclinical Data Support This Therapeutic Strategy?

Abstract

Recognition of the cytoprotective functions of autophagy that occur in tumor cells exposed to various forms of chemotherapy or radiation has generated intense interest in the possibility that pharmacological interference with autophagy could provide a clinical strategy for overcoming therapeutic resistance. Multiple clinical trials are currently in progress to evaluate the antimalarial agent chloroquine (generally in its clinical formulation as hydroxychloroquine) and its impact on various forms of cancer therapy. In this commentary/review, we focus on the relatively limited number of studies in the literature where chloroquine has been tested in combination with chemotherapy or radiation in experimental tumor-bearing animal models. We also present recent data from our own laboratories, in cell culture experiments as well as in vivo studies, which demonstrate that neither chloroquine nor silencing of an autophagy regulatory gene was effective in conferring radiation sensitivity in an experimental model of breast cancer. The capacity for sensitization by chloroquine appears to be quite wide-ranging, with dramatic effects for some drugs/tumor models and modest or minimal effects in others. One possible caveat is that, with only a few exceptions, experiments have generally been performed in xenograft models, thereby eliminating the involvement of the immune system, which might ultimately be proven to play a central role in determining the effectiveness of autophagy inhibition in chemosensitization or radiosensitization. Nevertheless, a careful review of the current literature suggests that caution is likely to be warranted in translating preclinical findings relating to autophagy inhibition as an adjunctive therapeutic strategy.

p62/Sequestosome-1 Up-regulation Promotes ABT-263-induced Caspase-8 Aggregation/Activation on the Autophagosome

“…Because autophagy inhibition results in the up-regulation of p62 proteins that are normally degraded by autophagy (41), our data provide a mechanism by which autophagy inhibitors, including chloroquine (11,16,(42)(43)(44) or bortezomib, can sensitize cancer cells to chemotherapy-induced apoptosis. In addition to chloroquine, recent data indicate that bortezomib can also inhibit autophagy via a cathepsin-dependent mechanism that results in p62 up-regulation (12).…”

Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy

“…43 However, a controversy exists in terms of chloroquine efficacy. 44 One explanation is that normal cells also use autophagy to maintain homeostasis, and inhibition of autophagy by chloroquine would also sensitize healthy organs such as kidneys to chemotherapy resulting in severe side effects. 45 Given that basal levels of EGR1 and MIR152 are relatively high in normal cells, activation of the EGR1-MIR152 pathway may not affect signaling of normal cells, but will greatly increase the therapeutic response in cancer cells.…”

Cytoprotective and nonprotective autophagy in cancer therapy

“…In a recent publication, 7 Dr. Andrew Thorburn and I have postulated the existence of another form of autophagy that will be termed "nonprotective." More specifically, we have observed induction by radiation of a form of autophagy whose inhibition neither sensitizes nor protects the tumor cell from radiation.…”

“…Leaving aside the vexing question of what would be the most appropriate animal models (xenografts vs. syngeneic vs. transgenic vs. carcinogen-induced, among others), the data in tumor-bearing animals treated with chemotherapy and the autophagy inhibitor chloroquine, is at best equivocal, as described in some detail in our recent paper. 7 That is, in approximately half the studies in the literature, the inclusion of chloroquine produces a modest or minimal increase in tumor growth delay over and above that of the therapeutic modality alone. In our own work, chloroquine fails to improve the response to radiation in a syngeneic model (4T1 cells) of breast cancer.…”