Abstract
Resident cancer cells with stem cell-like features induce drug tolerance, facilitating survival of glioblastoma (GBM). We previously showed that strategies targeting tumor bioenergetics present a novel emerging avenue for treatment of GBM. The objective of this study was to enhance the therapeutic effects of dual inhibition of tumor bioenergetics by combination of gossypol, an aldehyde dehydrogenase inhibitor, and phenformin, a biguanide compound that depletes oxidative phosphorylation, with the chemotherapeutic drug, temozolomide (TMZ), to block proliferation, stemness, and invasiveness of GBM tumorspheres (TSs). Combination therapy with gossypol, phenformin, and TMZ induced a significant reduction in ATP levels, cell viability, stemness, and invasiveness compared to TMZ monotherapy and dual therapy with gossypol and phenformin. Analysis of differentially expressed genes revealed up-regulation of genes involved in programmed cell death, autophagy, and protein metabolism and down-regulation of those associated with cell metabolism, cycle, and adhesion. Combination of TMZ with dual inhibitors of tumor bioenergetics may, therefore, present an effective strategy against GBM by enhancing therapeutic effects through multiple mechanisms of action.
Highlights
Despite improved standards of care, the survival rate of patients with glioblastoma (GBM) remains poor [1,2]
Resident cancer cells with stem cell-like features and heterogeneity induce therapeutic tolerance and relapse, facilitating glioblastoma (GBM) survival and proliferation characterized by GBM tumorspheres (TSs) [3,4,5,6,7]
Gossypol is a polyphenolic compound extracted from cottonseed known to exert anticancer effects by inhibiting aldehyde dehydrogenase (ALDH) and oxidative phosphorylation [20,21]
Summary
Despite improved standards of care, the survival rate of patients with glioblastoma (GBM) remains poor [1,2]. Resident cancer cells with stem cell-like features and heterogeneity induce therapeutic tolerance and relapse, facilitating glioblastoma (GBM) survival and proliferation characterized by GBM tumorspheres (TSs) [3,4,5,6,7]. Modulation of cancer cell metabolism through depletion of glucose and oxidative phosphorylation, the main source of tumor energy, is one such novel approach [9,10]. Combining several therapeutic agents to inhibit multiple energy pathways may present a means to induce synergistic activity against resistant cancer cells [11,12]. Metformin and phenformin are biguanides reported to induce energetic stress and glucose depletion by inhibiting mitochondrial complex I and oxidative phosphorylation [7,13,14,15,16,17]. Gossypol alone appears ineffective as a therapeutic agent for cancer [22,23,24]
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