Emerging strategies to effectively target autophagy in cancer

Abstract

Autophagy serves a dichotomous role in cancer and recent advances have helped delineate the appropriate settings where inhibiting or promoting autophagy may confer therapeutic efficacy in patients. Our evolving understanding of the molecular machinery responsible for the tightly controlled regulation of this homeostatic mechanism has begun to bear fruit in the way of autophagy-oriented clinical trials and promising lead compounds to modulate autophagy for therapeutic benefit. In this manuscript we review the recent preclinical and clinical therapeutic strategies that involve autophagy modulation in cancer.

Antitumor adaptive immunity remains intact following inhibition of autophagy and antimalarial treatment

“…Autophagy occurs both at basal conditions to maintain cellular homeostasis, and in response to environmental stresses such as nutrient starvation or hypoxia. Most studies investigating autophagy in cancer have focused on its cellintrinsic effects, including aiding cancer cell survival during extrinsic stress (2,3) as well as promoting drug resistance (4). Importantly, several clinical trials have combined traditional chemotherapy or targeted therapy with antimalarial lysosomotropic agents, such as hydroxychloroquine, which block the late stages of autophagic proteolysis (5)(6)(7)(8)(9)(10)(11)(12).…”

Out with the bad: Studying autophagy to fight infectious disease

“…In that case, they're looking for ways to inhibit instead of enhance autophagy. 8 Researchers have three more years of CETR funding to further dissect the role of autophagy in infectious disease. The "blue-sky" scenario would be to find a compound that could potentially work for viral, bacterial and parasitic infections, Virgin says.…”

Induction of mitophagy-mediated antitumor activity with folate-appended methyl-β-cyclodextrin

“…In brief, KB cells (1×10 6 ) were treated with RPMI-1640 medium (FA-free) containing 5 mM M-β-CyD or FA-M-β-CyD for 2 h. KB cells were homogenized in 4× sample buffer (8% sodium dodecyl sulfate, 40% glycerol, and 24% β-mercaptoethanol in Tris-HCl buffer, pH 6.8) and boiled for 5 min. The protein concentration was detected, with bovine serum albumin as standard, using the bicinchoninic acid reagent from Pierce Chemical (Rockford, IL, USA).…”

“…2,4,5 However, whether autophagy is protective or deleterious in cancer development has been widely debated. 6 Some clinical trials and nonclinical in vivo studies indicate that a lack of autophagy predisposes the tissues to develop tumors, possibly because autophagy normally moderates oxidative stress and DNA damage by removing defective mitochondria. However, in some mouse model studies, autophagy plays a crucial role in the growth of the tumors.…”