Aspirin Mitigated Tumor Growth in Obese Mice Involving Metabolic Inhibition

Abstract

Obesity is associated with a wide range of chronic diseases, including cancer. It has been noted that the integration of metabolic mechanisms in obese patients may predispose them to suffer from cancer incidence and its progression. Thus, a better understanding of metabolic alterations in obesity, along with the development of feasible therapeutic approaches for intervention, are theoretically relevant to the prevention and treatment of cancer malignancy. Using a syngeneic tumor model involving Lewis Lung Carcinoma (LLC) cells and C57BL/6 mice fed with a high fat diet, obesity was found to be associated with dysregulated glucose and glutamine metabolism, inflammation, along with platelet activation and the promotion of tumor growth. Tumor-bearing lowered glucose levels while moderately increasing inflammation, platelet activation, and glutamine levels. The antiplatelet drug aspirin, mitigated tumor growth in obese mice, paralleled by a decrease in systemic glucose, insulin, inflammation, platelet activation, glutamine and tumor expression of cell proliferation, aerobic glycolysis, glutaminolysis, platelets, and leukocyte molecules. The anti- and pro-cell proliferation, aerobic glycolysis, and glutaminolysis effects of aspirin and glutamine were further demonstrated in a LLC cell study. Although there remains limitations to our experiments, glucose and glutamine metabolism are proposed targets for the anticancer effects of aspirin.

Exosomal HMGB1 Promoted Cancer Malignancy

“…Previously, we reported that aspirin mitigated tumor growth in vivo [ 20 ]. To further extend in vitro findings with respect to antiplatelet drugs and exosomes, the effects of dipyridamole and GW4869, an inhibitor of exosome release [ 26 ], were explored in C57BL/6-LLC tumor-bearing mice.…”

“…Phosphodiesterase inhibitors increase the efficacy of anticancer drugs by promoting endocytosis-mediated cellular drug uptake [ 37 ]. We have demonstrated that aspirin induced endoplasmic reticulum stress-increased Noxa upregulation, restored ABT-737 apoptosis, and impaired glucose and glutamine metabolism in cancer cells [ 18 , 19 , 20 ]. In this study, aspirin and dipyridamole caused cell apoptosis and sensitized cells to doxorubicin-induced apoptosis.…”

“…Their tumors were resected for measurement and analyses. Tumor volume was calculated according to the following formula: V = (L × W 2 )/2 (L = length; W = width) [ 20 ].…”

“…The aforementioned findings suggest that HMGB1 could be an action target of antiplatelet drugs involving the disruption of reciprocal interaction between platelets and cancer cells. Previously, we reported the anticancer effects of aspirin through apoptosis, growth arrest, metabolic inhibition, and platelet cargo reduction, such as soluble P-selectin (sP-selectin) and TGF- β1 [ 18 , 19 , 20 ]. To continue and extend our research concentrating on reciprocal crosstalk between platelets and cancer cells, as well as anticancer potential of antiplatelet drugs, human chronic myeloid leukemia K562 cell-differentiated megakaryocytes, human bladder cancer T24 cells, murine platelets, murine Lewis lung carcinoma (LLC) cells, and C57BL/6-LLC tumor-bearing mice models were established and subjected to antiplatelet drug treatment.…”

High-fat diet-induced obesity primes fatty acid β-oxidation impairment and consequent ovarian dysfunction during early pregnancy

“…Hyperglycemia and dyslipidemia are 2 metabolic alterations of obesity, a condition which is associated with dysregulation of glucose and fatty acid metabolism in tissues and organs (18). To shed light on the possible mechanism by which HFDinduced obesity impairs ovarian function during early pregnancy, we first explored whether glycolysis, the central pathway of glucose metabolism (19), is affected by obesity.…”