Ascorbate sensitizes human osteosarcoma cells to the cytostatic effects of cisplatin

Abstract

Osteosarcoma (OS) is the most common malignant bone tumor and a leading cause of cancer‐related deaths in children and adolescents. Current standard treatments for OS are a combination of preoperative chemotherapy, surgical resection, and adjuvant chemotherapy. Cisplatin is used as the standard chemotherapeutic for OS treatment, but it induces various adverse effects, limiting its clinical application. Improving treatment efficacy without increasing the cisplatin dosage is desirable. In the present study, we assessed the combined effect of ascorbate on cisplatin treatment using cultured human OS cells. Co‐treatment with ascorbate induced greater suppression of OS cell but not nonmalignant cell proliferation. The chemosensitizing effect of ascorbate on cisplatin treatment was tightly linked to ROS production. Altered cellular redox state due to increased ROS production modified glycolysis and mitochondrial function in OS cells. In addition, OS cell sphere formation was markedly decreased, suggesting that ascorbate increased the treatment efficacy of cisplatin against stem‐like cells in the cancer cell population. We also found that enhanced MYC signaling, ribosomal biogenesis, glycolysis, and mitochondrial respiration are key signatures in OS cells with cisplatin resistance. Furthermore, cisplatin resistance was reversed by ascorbate. Taken together, our findings provide a rationale for combining cisplatin with ascorbate in therapeutic strategies against OS.

The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer

“…Baicalein deteriorates hypoxia-induced 5-FU resistance in gastric cancer by suppressing glycolysis and the PTEN/AKT/HIF-1 signaling pathway (199). Ascorbate combined with cisplatin increases ROS production and alters glycolysis and mitochondrial function by decreasing the HIF-1 activity, which further restores cisplatin sensitivity of osteosarcoma (200).…”

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

“…Triptolide promotes intracellular accumulation of ROS to inhibit NF-κB signaling and down-regulate Bcl-2 and X-linked inhibitor of apoptosis protein (XIAP) as anti-apoptotic factors, increasing CP sensitivity of ovarian cancer cells [237]. Reducing glycolysis (Warburg effect) and impairing mitochondrial function are induced by ascorbate in increasing CP sensitivity of osteosarcoma cells (Figure 3) [238]. Overall, the following points can be concluded about using anti-tumor compounds, which are mostly phytochemicals and have roles in enhancing CP sensitivity of cancer cells: Most of the anti-tumor compounds applied with CP in cancer chemotherapy are plant derived-natural products, and one of their drawbacks is their poor bioavailability that can be overcome using nanoparticles.…”

Biological evidence of cancer stem-like cells and recurrent disease in osteosarcoma

“…Similarly, ROCK inhibition by fasudil suppressed in vitro cell BMP2 BMP2 receptor signaling [110] Other receptor signaling targeting (STAT-3, STAT-5, ER-α, TRAF-2, etc.) and transcription factors Bruceine D STAT-3 inhibition [111] Pimozide STAT-5 signaling [75,112] Decitabine Activation of estrogen receptor alpha (ER-α) [113] NCB-0846 TRAF2-and NCK-interacting protein kinase [114] Melatonin Suppression of SOX9 mediated signaling [115] Statins KLF4 [116] Targeting of kinase activities Fasudil Rho-associated coiled-coil containing kinase (ROCK) inhibition [100] Autophagy and metabolic targeting Thioridazine Autophagy [94] -Inhibition of mitochondrial functions (decrease in oxygen assumption, decreased mitochondrial membrane potential, decreased ATP production) [117] -Pyruvate kinase isoenzyme M2 (PKM2) [118] -ROS-mediated apoptosis and autophagy [119] Metfomin -Activation and phosphorylation of the energetic sensor AMPK [120] Wogonin ROS regulation [121] DMAMCL Cell cycle [122] DAPT γ-secretase inhibition [123] Combinations with chemotherapy and sensitization to chemotherapy Ascorbate Sensitization to cisplatin [124] Ouabain Sensitization to cisplatin: Na + /K + ATPase inhibition [125] Tangeretin -Disruption of the DNMT1/miR34a/Bcl-2 axis by isovitexin [85] -lncRNA HOXD-AS1 knockdown [92] -RAB39A silencing [99] Epigenetic targeting -Targeting of lncRNA SOX2OT variant 7 by EGCG (polyphenol isolated from green tea) [130] Photo therapy -Graphene oxide nanoparticle-loaded ginsenoside Rg3…”

“…For instance, thioridazin and metformin target autophagy and metformin and wogomin modulated ROSmediated apoptosis in CSCs and resensitize CSCs to cell death [114][115][116] . Similarly, regulation of cell cycle by DMAMCL or inhibition of γ-secretase by DAPT affects the behavior of CSCs and their function in tumor growth [122,123] .…”

“…Drugs/effective agents can be used as sensitization agents to chemotherapy [ 124 , 125 ] or in combination with chemotherapeutic drugs [ 126 , 127 ] . Numerous cytokines are involved in the control of local immunity of cancer cells [ 128 ] and immunotherapies have been proposed for targeting CTCs [ 129 ] .…”