Targeting 6-phosphogluconate dehydrogenase in the oxidative PPP sensitizes leukemia cells to antimalarial agent dihydroartemisinin

Abstract

The oxidative pentose phosphate pathway (PPP) is crucial for cancer cell metabolism and tumor growth. We recently reported that targeting a key oxidative PPP enzyme, 6-phosphogluconate dehydrogenase (6PGD), using our novel small molecule 6PGD inhibitors Physcion and its derivative S3, shows anti-cancer effects. Notably, humans with genetic deficiency of either 6PGD or another oxidative PPP enzyme, glucose-6-phosphate dehydrogenase (G6PD), exhibit non-immune hemolytic anemia upon exposure to aspirin and various anti-malarial drugs. Inspired by these clinical observations, we examined the anti-cancer potential of combined treatment with 6PGD inhibitors and anti-malarial drugs. We found that stable knockdown of 6PGD sensitizes leukemia cells to anti-malarial agent dihydroartemisinin (DHA). Combined treatment with DHA and Physcion activates AMP-activated protein kinase, leading to synergistic inhibition of human leukemia cell viability. Moreover, our combined therapy synergistically attenuates tumor growth in xenograft nude mice injected with human K562 leukemia cells and cell viability of primary leukemia cells from human patients, but shows minimal toxicity to normal hematopoietic cells in mice as well as red blood cells and mononucleocytes from healthy human donors. Our findings reveal the potential for combined therapy using optimized doses of Physcion and DHA as a novel anti-leukemia treatment without inducing hemolysis.

Expression of Pentose Phosphate Pathway-Related Proteins in Breast Cancer

“…The clinical implication of this study is the identification of the PPP protein as a potential therapeutic target. Previous studies reported that inhibition of PPP proteins resulted in growth inhibition and cell death in leukemia [ 31 ], ovary cancer [ 32 ], urinary bladder cancer [ 33 ], and breast cancer/prostate cancer [ 34 ], suggesting that modulation of this pathway may have therapeutic potential in the treatment of cancer.…”

Inhibition of Glucose-6-Phosphate Dehydrogenase Reverses Cisplatin Resistance in Lung Cancer Cells via the Redox System

“…Due to the abnormal demands of proliferation, the phenomenon of a hyperactive PPP usually manifests itself in many cancers, such as lung cancer, liver cancer, pancreas cancer and leukemia ( Ying et al, 2010 ; Lin et al, 2015 ; Kowalik et al, 2017 ; Elf et al, 2017 ), and the oxidative branch plays a predominant part, since it regulates redox homeostasis by generating NADPH. NADPH is a common molecule required in the biosynthesis of fatty acids and cholesterol and the generation of reduced glutathione (GSH).…”

Apoptotic effect of physcion isolated from marine fungus Microsporum sp. in PC3 human prostate cancer cells

“…Recently, Pang's group found that physcion induces apoptosis and autophagy in human nasopharyngeal carcinoma cells CNE2 by targeting Sp1, which is mediated by ROS/mir-27a/ZBTB10 signaling (2016). Besides solid tumor, physcion has been also investigated on hematological malignancies (Liu et al 2016;Elf et al 2017). Physcion sensitizes human leukemia cells to antimalarial agent dihydroartemisinin (Elf et al 2017) and to reverse multidrug resistance in human chronic myelogenous leukemia K562/AMD cells (Liu et al 2016).…”

“…Besides solid tumor, physcion has been also investigated on hematological malignancies (Liu et al 2016;Elf et al 2017). Physcion sensitizes human leukemia cells to antimalarial agent dihydroartemisinin (Elf et al 2017) and to reverse multidrug resistance in human chronic myelogenous leukemia K562/AMD cells (Liu et al 2016). Therefore, physcion may be able to target multiple molecules to exert anti-tumor effect in various cell types.…”