Dichloroacetic acid and rapamycin synergistically inhibit tumor progression

by Selleckchem | Aug 15 2023

Mammalian target of rapamycin (mTOR) controls cellular anabolism, and mTOR signaling is hyperactive in most cancer cells. As a result, inhibition of mTOR signaling benefits cancer patients. Rapamycin is a US Food and Drug Administration (FDA)-approved drug, a specific mTOR complex 1 (mTORC1) inhibitor, for the treatment of several different types of cancer. However, rapamycin is reported to inhibit cancer growth rather than induce apoptosis. Pyruvate dehydrogenase complex (PDHc) is the gatekeeper for mitochondrial pyruvate oxidation. PDHc inactivation has been observed in a number of cancer cells, and this alteration protects cancer cells from senescence and nicotinamide adenine dinucleotide (NAD+‍) exhaustion. In this paper, we describe our finding that rapamycin treatment promotes pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) phosphorylation and leads to PDHc inactivation dependent on mTOR signaling inhibition in cells. This inactivation reduces the sensitivity of cancer cells' response to rapamycin. As a result, rebooting PDHc activity with dichloroacetic acid (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, promotes cancer cells' susceptibility to rapamycin treatment in vitro and in vivo.

Comments:

The passage you provided describes a research finding regarding the relationship between the mammalian target of rapamycin (mTOR) signaling pathway, pyruvate dehydrogenase complex (PDHc) activity, and the response of cancer cells to rapamycin treatment.

mTOR is a protein kinase that plays a crucial role in regulating cellular processes such as growth, proliferation, and metabolism. Hyperactivation of mTOR signaling is commonly observed in cancer cells and contributes to their abnormal growth and survival.

Rapamycin is an FDA-approved drug known to inhibit a specific complex of mTOR called mTORC1. It has been used for the treatment of various types of cancer. However, its mechanism of action primarily involves inhibiting cancer cell growth rather than directly inducing apoptosis (programmed cell death).

The researchers in this study found that rapamycin treatment leads to the phosphorylation of the pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), a component of the PDHc. This phosphorylation event resulted in the inactivation of PDHc, which is responsible for facilitating the oxidation of pyruvate within mitochondria. The inactivation of PDHc has been observed in many cancer cells and is associated with protecting the cells from senescence (cellular aging) and depletion of nicotinamide adenine dinucleotide (NAD+).

Importantly, the study revealed that the inactivation of PDHc induced by rapamycin treatment reduced the sensitivity of cancer cells to the drug. To overcome this resistance, the researchers explored the use of dichloroacetic acid (DCA), a compound that inhibits pyruvate dehydrogenase kinase (PDK). PDK is an enzyme that phosphorylates and inactivates PDHc. By inhibiting PDK with DCA, the researchers were able to reactivate PDHc and enhance the susceptibility of cancer cells to rapamycin treatment both in vitro (in cell culture) and in vivo (in animal models).

Overall, the study suggests that combining rapamycin with DCA, which targets the PDHc pathway, may be a potential strategy to improve the effectiveness of rapamycin treatment in certain cancer types. However, it's important to note that further research is needed to validate these findings and explore the potential clinical implications of this combination therapy.