Glucose Conferred Irinotecan Chemoresistance through Divergent Actions of Pyruvate and ATP in Cell Death and Proliferation of Colorectal Cancer

Abstract

Altered glucose metabolism is associated with chemoresistance in colorectal cancer (CRC). This study aimed to illustrate the molecular mechanisms of glucose-mediated chemoresistance against irinotecan, a topoisomerase I inhibitor, focusing on the distinct roles of metabolites such as pyruvate and ATP in modulating cell death and proliferation. Four human CRC cell lines, tumorspheres, and mouse xenograft models were treated with various doses of irinotecan in the presence of high concentrations of glucose, pyruvate, or ATP-encapsulated liposomes. In this study, human CRC cell lines treated with irinotecan in high glucose displayed increased cell viability and larger xenograft tumor sizes in mouse models compared to those treated in normal glucose concentrations. Irinotecan induced apoptosis and necroptosis, both mitigated by high glucose. Liposomal ATP prevented irinotecan-induced apoptosis, while it did not affect necroptosis. In contrast, pyruvate attenuated the receptor-interacting protein kinase (RIP) 1/3-dependent necroptosis via free radical scavenging without modulating apoptotic levels. Regarding the cell cycle, liposomal ATP aggravated irinotecan-induced G0/G1 shift, whereas pyruvate diminished the G0/G1 shift, showing opposite effects on proliferation. Last, tumorsphere structural damage, an index of solid tumor responsiveness to chemotherapy, was determined. Liposomal ATP increased tumorsphere size while pyruvate prevented the deformation of spheroid mass. In conclusion, glucose metabolites confer tumor chemoresistance via multiple modes of action. Glycolytic pyruvate attenuated irinotecan-induced necroptosis and potentiated drug insensitivity by shifting cells from a proliferative to quiescent state. On the other hand, ATP decreased irinotecan-induced apoptosis and promoted active cell proliferation, contributing to tumor recurrence. Our findings challenged the traditional view of ATP as the main factor for irinotecan chemoresistance and provided novel insights of pyruvate acting as an antioxidant responsible for drug insensitivity, which may shed light to the development of new therapies against recalcitrant cancers.

Small Molecule‐Drug Conjugates: Opportunities for the Development of Targeted Anticancer Drugs

“…The clinical efficacy of irinotecan may be influenced by multiple resistance mechanisms, a recently reported mechanism suggests that pyruvate, a glucose metabolite, may diminishes Irinotecaninduced necrosis thus enhancing drug insensitivity. [82] On the other hand, ATP also diminishes irinotecan-induced apoptosis according to conventional perspectives. [82] Therefore, recent research synthesized a series of SMDCs that conjugating glucose transporter inhibitors (phlorizin or phloretin) with SN38 by utilizing two distinct linkers: disulfide bonds sensitive to GSH and valine-citrulline-para aminobenzyl alcohol (ValÀ CitÀ PABÀ OH) cleavable by cathepsin B.…”

Design, Synthesis, and Evaluation of Glucose Transporter Inhibitor-SN38 Conjugates for Targeting Colorectal Cancer

“…After 1.5 h, the solvent in the mixture was evaporated to dryness in vacuo, and the resulting residue was purified via column chromatography (silica gel; DCM/MeOH = 7/1−5/1) to yield compound 9 (113 mg, 50%) as a yellow solid. 1 (2S)-N-(4-((((S)-4,11-Diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizinol [1,2-b] (10). Compound 15 (21.5 mg, 0.05 mmol) was mixed with a solution of compound 17 (36 mg, 0.04 mmol) in MeOH (20 mL).…”

“…This mechanism for resistance was reported recently, and few measures exist to counter this resistance. Glucose conferred irinotecan chemoresistance through divergent actions of pyruvate and ATP to modulate cell death and proliferation of CRC cells and glucose restriction can enhance the sensitivity to irinotecan; , therefore, designing conjugates comprising a glucose transporter inhibitor and SN38 to create new prodrugs may be a promising approach for improving CRC therapy.…”

“…Multiple mechanisms for irinotecan resistance may attenuate its clinical response rate, including low topoisomerase-I expression, mutations in the topoisomerase-I gene, active efflux-induced low intracellular drug levels, and glucose metabolite-mediated drug insensitivity. , Strategies for overcoming the above-mentioned drug resistance have been widely studied, except for the glucose-related resistance toward irinotecan. This mechanism for resistance was reported recently, and few measures exist to counter this resistance.…”

Cola rostrata K. Schum. constituents induce cytotoxicity through reactive oxygen species generation and mitochondrial membrane depolarisation

“…Cancer is a disease characterized by uncontrolled proliferation of cells, deranged cellular metabolism, progressive genetic instability, de-differentiation of cells, and metastasis, which, if not detected early enough and appropriately treated, results in death [ 1 , 2 ]. Currently, cancer is a leading cause of death globally, owing, in part, to its cellular plasticity and increasing chemoresistance to current, clinically used anticancer drugs [ 3 , 4 ]. The plethora of unwanted side effects of most chemotherapeutic drugs in use today and their declining effectiveness due to resistance mechanisms in cancer cells have made the discovery of more tolerable anticancer drugs, which are less susceptible to chemoresistance, incumbent and urgent.…”