The Anticancer Ruthenium Compound BOLD-100 Targets Glycolysis and Generates a Metabolic Vulnerability towards Glucose Deprivation.

Dina Baier,Evelyn Rampler,Martin Schaier,Walter Berger,Christine Pirker,Bernhard Keppler,Katharina Hohenwallner,Theresa Mendrina,Mate Rusz,Thomas Mohr,Beatrix Schoenhacker-Alte,Dominik Kirchhofer,Gunda Koellensperger,Samuel M Meier-Menches,Petra Heffeter

doi:10.3390/pharmaceutics14020238

Dina Baier, Evelyn Rampler + Show 13 more

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https://doi.org/10.3390/pharmaceutics14020238

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Abstract

Cellular energy metabolism is reprogrammed in cancer to fuel proliferation. In oncological therapy, treatment resistance remains an obstacle and is frequently linked to metabolic perturbations. Identifying metabolic changes as vulnerabilities opens up novel approaches for the prevention or targeting of acquired therapy resistance. Insights into metabolic alterations underlying ruthenium-based chemotherapy resistance remain widely elusive. In this study, colon cancer HCT116 and pancreatic cancer Capan-1 cells were selected for resistance against the clinically evaluated ruthenium complex sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (BOLD-100). Gene expression profiling identified transcriptional deregulation of carbohydrate metabolism as a response to BOLD-100 and in resistance against the drug. Mechanistically, acquired BOLD-100 resistance is linked to elevated glucose uptake and an increased lysosomal compartment, based on a defect in downstream autophagy execution. Congruently, metabolomics suggested stronger glycolytic activity, in agreement with the distinct hypersensitivity of BOLD-100-resistant cells to 2-deoxy-d-glucose (2-DG). In resistant cells, 2-DG induced stronger metabolic perturbations associated with ER stress induction and cytoplasmic lysosome deregulation. The combination with 2-DG enhanced BOLD-100 activity against HCT116 and Capan-1 cells and reverted acquired BOLD-100 resistance by synergistic cell death induction and autophagy disturbance. This newly identified enhanced glycolytic activity as a metabolic vulnerability in BOLD-100 resistance suggests the targeting of glycolysis as a promising strategy to support BOLD-100 anticancer activity.

Highlights

The reprogramming of cellular energy metabolism characterizes a hallmark of diverse types of cancer to efficiently fuel biomass production and sustain cell proliferation [1]
Since BOLD-100 is currently being investigated clinically (NCT04421820) and the development of chemotherapy resistance remains a major hurdle in cancer treatment [53,54], this study aimed to characterize the mechanisms underlying acquired BOLD-100 resistance
The selection resulted in 2.2-fold increased BOLD-100 resistance in HCTR (IC50 of HCTR vs. HCT116 cells) and a 4.1-fold increased resistance in CapanR

Summary

Introduction

The reprogramming of cellular energy metabolism characterizes a hallmark of diverse types of cancer to efficiently fuel biomass production and sustain cell proliferation [1]. In the development of anticancer therapy resistance, cellular metabolism, for example, glycolytic activity, is often further enhanced [5] In this regard, several combined or independently emerging mechanisms have been identified, including (1) the upregulated expression of (rate-limiting) enzymes of the glycolytic pathway [2,6], such as hexokinase 2 (HK2) and phosphofructokinases (PFK), (2) enhanced expression of glucose transporters (GLUT) [7,8,9], (3) aberrant activity of signaling pathways sensing the metabolic state [10,11], and (4) Myc-induced metabolic reprogramming [12,13]. Enhanced cellular glycolytic activity confers a poor prognosis in patients suffering from diverse types of solid tumors [5,7,8] This increased and vital glycolytic activity in (therapy-resistant) cancer cells translates into an exploitable vulnerability [14] and, provides a rational therapy target

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