The novel phloroglucinol PMT7 kills glycolytic cancer cells by blocking autophagy and sensitizing to nutrient stress

Abstract

The switch from oxidative phosphorylation to glycolytic metabolism results in cells that generate fewer reactive oxygen species (ROS) and are resistant to the intrinsic induction of apoptosis. As a consequence, glycolytic cancer cells are resistant to radiation and chemotherapeutic agents that rely on production of ROS or intrinsic apoptosis. Further, the level of glycolysis correlates with tumor invasion, making glycolytic cancer cells an important target for new therapy development. We have synthesized a novel redox-active quinone phloroglucinol derivative, PMT7. Toxicity of PMT7 was in part due to loss of mitochondrial membrane potential in treated cells with subsequent loss of mitochondrial metabolic activity. Mitochondrial gene knockout ρ0 cells, a model of highly glycolytic cancers, were only half as sensitive as the corresponding wild-type cells and metabolic pathways downstream of MET were unaffected in ρ0 cells. However, PMT7 toxicity was also due to a block in autophagy. Both wild-type and ρ0 cells were susceptible to autophagy blockade, and the resistance of ρ0 cells to PMT7 could be overcome by serum deprivation, a situation where autophagy becomes necessary for survival. The stress response class III deacetylase SIRT1 was not significantly involved in PMT7 toxicity, suggesting that unlike other chemotherapeutic drugs, SIRT1-mediated stress and survival responses were not induced by PMT7. The dependence on autophagy or other scavenging pathways makes glycolytic cancer cells vulnerable. This can be exploited by induction of energetic stress to specifically sensitize glycolytic cells to other stresses such as nutrient deprivation or potentially chemotherapy.

Targeting Cancer Cell Mitochondria as a Therapeutic Approach

“…Its anticancer activity seems due in part to the induction of mitochondria tmembrane potential loss and the subsequent loss of mitochondrial metabolic activity [44]. Mitochondrial respiration-defective p 0 cells were less sensitive to this compound compared with corresponding wild-type cells.…”

Anticancer Properties and Mechanism of Action of Oblongifolin C, Guttiferone K and Related Polyprenylated Acylphloroglucinols

“…Phloroglucinol (1,3,5 tri-hydroxy-benzene) is a musculotropic anti-spasmodic drug, prescribed (in the European Union) for alleviating abdominal pain [ 98 ]. Phloroglucinol can induce the formation of autophagosomes in follicle cells [ 99 ] and an anticancer phloroglucinol derivative (PMT7) was found to kill glycolytic cancer cells by blocking autophagy [ 100 ]. Moreover, the apple dihydrochalcone phloretin, which possesses a phloroglucinol moiety linked to phenol side chain, is also an autophagy-inducer active against drug-resistant cancer cell lines [ 101 ], as observed with Ob-C [ 58 ].…”

Mitochondrial Ca2+ Remodeling is a Prime Factor in Oncogenic Behavior

“…Some of these drugs may affect mitochondrial Ca 2+ uptake due to the depolarization of ΔΨ. The compounds included in this category are as follows: pancratistatin (a natural alkaloid exhibiting anti-cancer effects against human colorectal adenocarcinoma xenografts ( 92 ) and colorectal carcinoma cell lines, rhodamine-123 [the anti-cancer effects of rhodamine-123 can be explained by its higher retention in kidney and breast cancer cells compared to non-tumorigenic cells ( 93 , 94 )], a naphthyridine derivative [4-phenyl-2,7-di(piperazin-1-yl)-1,8-naphthyridine ( 95 )], PMT7 [redox-active quinone phloroglucinol derivative ( 96 )], edelfosine [1- O -octadecyl-2- O -methyl-racglycero-3-phosphocholine; its redistribution to the mitochondria in HeLa cells causes mitochondrial depolarization and apoptosis ( 97 )], and many others that inhibit the mitochondrial respiratory chain that have been reviewed in detail by Wen et al ( 98 ).…”