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

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.

The copper transporter CTR1 and cisplatin accumulation at the single-cell level by LA-ICP-TOFMS

“…Cells were seeded in 6-well plates (7 × 10 5 cells/well), incubated for 24 h and then exposed to 10 µM cisplatin for 6 h. Cells were harvested and proteins were isolated as described previously ( Baier et al, 2022 ). Polyvinylidene difluoride membranes were incubated for 18 h while shaking at 4°C in TBS/0.1% Tween/3% BSA containing the following primary antibodies: anti-CTR1 rabbit polyclonal antibody (#sc-66847, 1:500), purchased from Santa Cruz Biotechnology (Dallas, TX, United States) and anti-beta-Actin mouse monoclonal antibody (#A5441, 1:2,000), purchased from Sigma-Aldrich.…”

Synthetic Small Molecule Modulators of Hsp70 and Hsp40 Chaperones as Promising Anticancer Agents

“…CHOP and XPB1 expression were upregulated by compound 22 in REN cells. Sensitive HCT-116 colon carcinoma (IC 50 = 76 µM) and Capan1 pancreatic carcinoma cells (IC 50 = 40 µM) were used to study cell-based resistance to treatment with compound 22 [ 88 ]. Increased glucose uptake and upregulated glycolysis were observed in sensitive cancer cells upon treatment, but especially in the resistant cell lines HCTR and CapanR obtained from HCT-116 and Capan1 cells, respectively, upon exposure to compound 22 .…”

Targeting of the intracellular redox balance by metal complexes towards anticancer therapy

“…NAMI-A was successfully studied in phase I, but poor efficacy was obtained in phase II, while the low solubility of related compound KP1019 limited further development (Figure 3). (Alessio and Messori, 2019;Bergamo and Sava, 20072007;Baier et al, 2022;a;Monro et al, 2019) Ruthenium(III) KP-1339 is currently undergoing clinical trials, delivering promising Ib phase data for anticancer activity. Ruthenium(II) complex TLD-1433 acts as a photosensitizer, and is currently being evaluated in phase II for photodynamic therapy (PDT) against human non-muscle invasive bladder cancer.…”

“…NAMI-A was successfully studied in phase I, but poor efficacy was obtained in phase II, while the low solubility of related compound KP1019 limited further development ( Figure 3 ). ( Alessio and Messori, 2019 ; Bergamo and Sava, 20072007 ; Baier et al, 2022 ; a; Monro et al, 2019 )…”