BAY 87‐2243, a highly potent and selective inhibitor of hypoxia‐induced gene activation has antitumor activities by inhibition of mitochondrial complex I

Abstract

The activation of the transcription factor hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor development, tumor progression, and resistance to chemo- and radiotherapy. In order to identify compounds targeting the HIF pathway, a small molecule library was screened using a luciferase-driven HIF-1 reporter cell line under hypoxia. The high-throughput screening led to the identification of a class of aminoalkyl-substituted compounds that inhibited hypoxia-induced HIF-1 target gene expression in human lung cancer cell lines at low nanomolar concentrations. Lead structure BAY 87-2243 was found to inhibit HIF-1α and HIF-2α protein accumulation under hypoxic conditions in non-small cell lung cancer (NSCLC) cell line H460 but had no effect on HIF-1α protein levels induced by the hypoxia mimetics desferrioxamine or cobalt chloride. BAY 87-2243 had no effect on HIF target gene expression levels in RCC4 cells lacking Von Hippel–Lindau (VHL) activity nor did the compound affect the activity of HIF prolyl hydroxylase-2. Antitumor activity of BAY 87-2243, suppression of HIF-1α protein levels, and reduction of HIF-1 target gene expression in vivo were demonstrated in a H460 xenograft model. BAY 87-2243 did not inhibit cell proliferation under standard conditions. However under glucose depletion, a condition favoring mitochondrial ATP generation as energy source, BAY 87-2243 inhibited cell proliferation in the nanomolar range. Further experiments revealed that BAY 87-2243 inhibits mitochondrial complex I activity but has no effect on complex III activity. Interference with mitochondrial function to reduce hypoxia-induced HIF-1 activity in tumors might be an interesting therapeutic approach to overcome chemo- and radiotherapy-resistance of hypoxic tumors.

Clinically Evaluated Cancer Drugs Inhibiting Redox Signaling

“…Under conditions of glucose depletion that favor mitochondrial ATP generation in cancer cells as energy source, BAY 87-2243 inhibited cell proliferation in the nanomolar range (27). BAY 87-2243 interference with mitochondrial function resulted in reduced hypoxia-induced HIF-1 activity in tumors and prompted exploration of its use with radiation as a therapeutic approach to overcome chemo-and radiotherapy resistance of hypoxic tumors (45).…”

The Bioenergetic Role of Mitochondria in Lung Cancer

“…Thus, no methods are currently available to effectively treat these patients. However, several recent experiments strongly suggest that targeting mitochondria will yield effective strategies to treat lung cancer patients in the future [14][15][16][17][18].…”

“…Several studies have suggested that inhibiting mitochondrial function makes drug-resistant tumors more sensitive to treatment [14][15][16]18]. When oxidative phosphorylation was suppressed, cancer became less able to proliferate in an anchorage-independent manner [14].…”

“…Consequently, when the mitochondria of tumor cells are tampered with to inhibit oxidative phosphorylation, these tumor cells become significantly more susceptible to cytotoxic drugs [16,19]. Agents such as cyclopamine tartrate, a water-soluble derivative of a molecule found in corn lilies [20]; metformin, an antidiabetic drug [18]; BAY 87-2243, a lead structure [15]; and microRNA-126, a microRNA [21] have shown potential to interfere with normal mitochondrial function in cancer cells. These molecules interact with various aspects of mitochondrial function, such as interfering with Hedgehog signaling and inhibiting Complex I. Cyclopamine tartrate functions by inhibiting Hedgehog signaling [20].…”

Chapter 8. Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101

“…Developed by Bayer (Germany), BAY87-2243 is a potent HIF-1a and HIF-2a inhibitor with antitumour activity. 98 A phase I clinical study conducted to evaluate the MTD of BAY87-2243 in patients with advanced malignancies (ClinicalTrials.org identifier NCT01297530) was terminated due to unanticipated high toxicities.…”