The disubstituted adamantyl derivative LW1564 inhibits the growth of cancer cells by targeting mitochondrial respiration and reducing hypoxia-inducible factor (HIF)-1 alpha accumulation

Abstract

Cancer: Drug targets mitochondrial metabolism to inhibit tumor growth A drug that curbs the accumulation of a critical protein involved in the oxygen-sensing machinery of cells could offer a potent new therapeutic for treating cancer. Inhyub Kim, University of Science and Technology, Daejeon, South Korea, and colleagues describe a compound called LW1564 that suppresses metabolism within mitochondria, the energy factories of the cell. Less energy production means less oxygen consumption and therefore oxygen molecules build up inside the cell, which in turn stimulates the degradation of HIF-1 alpha, a master regulator of oxygen balance. Many tumors rely on HIF-1 alpha for their aberrant biological characteristics, and without this protein they tend to show reduced growth. The authors demonstrated that LW1564 could limit HIF-1 alpha accumulation and inhibit the proliferation of various cancer cell lines. The drug also inhibited tumor growth in a mouse model of liver cancer. Targeting cancer metabolism has emerged as an important cancer therapeutic strategy. Here, we describe the synthesis and biological evaluation of a novel class of hypoxia-inducible factor (HIF)-1 alpha inhibitors, disubstituted adamantyl derivatives. One such compound, LW1564, significantly suppressed HIF-1 alpha accumulation and inhibited the growth of various cancer cell lines, including HepG2, A549, and HCT116. Measurements of the oxygen consumption rate (OCR) and ATP production rate revealed that LW1564 suppressed mitochondrial respiration, thereby increasing the intracellular oxygen concentration to stimulate HIF-1 alpha degradation. LW1564 also significantly decreased overall ATP levels by inhibiting mitochondrial electron transport chain (ETC) complex I and downregulated mammalian target of rapamycin (mTOR) signaling by increasing the AMP/ATP ratio, which increased AMP-activated protein kinase (AMPK) phosphorylation. Consequently, LW1564 promoted the phosphorylation of acetyl-CoA carboxylase, which inhibited lipid synthesis. In addition, LW1564 significantly inhibited tumor growth in a HepG2 mouse xenograft model. Taken together, the results indicate that LW1564 inhibits the growth of cancer cells by targeting mitochondrial ETC complex I and impairing cancer cell metabolism. We, therefore, suggest that LW1564 may be a potent therapeutic agent for a subset of cancers that rely on oxidative phosphorylation for ATP generation.