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Published on: August 31, 2015
Oxidative pentose phosphate pathway inhibition is a key determinant of antimalarial induced cancer cell death
1Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Abstract:
Despite immense interest in using antimalarials as autophagy inhibitors to treat cancer, it remains unclear whether these agents act predominantly via autophagy inhibition or whether other pathways direct their anti-cancer properties. By comparing the treatment effects of the antimalarials chloroquine (CQ) and quinacrine (Q) on KRAS mutant lung cancer cells, we demonstrate that inhibition of the oxidative arm of the pentose phosphate pathway (oxPPP) is required for antimalarial induced apoptosis. Despite inhibiting autophagy, neither CQ treatment nor RNAi against autophagy regulators (ATGs) promote cell death. In contrast, Q triggers high levels of apoptosis, both in vitro and in vivo, and this phenotype requires both autophagy inhibition and p53-dependent inhibition of the oxPPP. Simultaneous genetic targeting of the oxPPP and autophagy is sufficient to trigger apoptosis in lung cancer cells, including cells lacking p53. Thus, in addition to reduced autophagy, oxPPP inhibition serves as an important determinant of antimalarial cytotoxicity in cancer cells.
Insights
Antimalarials like quinacrine induce cancer cell death by inhibiting the oxidative pentose phosphate pathway (oxPPP), not just autophagy. Targeting oxPPP and autophagy together triggers apoptosis, even in p53-deficient lung cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Antimalarials are investigated as cancer treatments, primarily for their autophagy-inhibiting effects.
- The precise mechanisms underlying their anti-cancer properties, beyond autophagy inhibition, require further elucidation.
Purpose of the Study:
- To compare the anti-cancer effects of chloroquine (CQ) and quinacrine (Q) on KRAS-mutant lung cancer cells.
- To determine the role of autophagy inhibition and the oxidative pentose phosphate pathway (oxPPP) in antimalarial-induced apoptosis.
Main Methods:
- Treatment of KRAS-mutant lung cancer cells with CQ and Q.
- RNA interference (RNAi) targeting autophagy regulators (ATGs).
- Assessment of apoptosis, autophagy inhibition, and oxPPP activity in vitro and in vivo.
Main Results:
- Neither CQ nor ATG-targeting RNAi induced significant apoptosis.
- Quinacrine (Q) triggered substantial apoptosis, dependent on both autophagy inhibition and p53-mediated oxPPP inhibition.
- Simultaneous genetic targeting of oxPPP and autophagy induced apoptosis in lung cancer cells, including p53-deficient ones.
Conclusions:
- Autophagy inhibition alone is insufficient for antimalarial-induced cancer cell death.
- Inhibition of the oxidative pentose phosphate pathway (oxPPP) is a critical mechanism for antimalarial cytotoxicity.
- Combined targeting of oxPPP and autophagy presents a potential therapeutic strategy for lung cancer, irrespective of p53 status.
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