Mechanisms of Doxorubicin Toxicity in Pancreatic β-Cells

Abstract

Exposure to chemotherapeutic agents has been linked to an increased risk of type 2 diabetes (T2D), a disease characterized by both the peripheral insulin resistance and impaired glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. Using the rat β-cell line INS-1 832/13 and isolated mouse pancreatic islets, we investigated the effect of the chemotherapeutic drug doxorubicin (Adriamycin) on pancreatic β-cell survival and function. Exposure of INS-1 832/13 cells to doxorubicin caused impairment of GSIS, cellular viability, an increase in cellular toxicity, as soon as 6 h post-exposure. Doxorubicin impaired plasma membrane electron transport (PMET), a pathway dependent on reduced equivalents NADH and NADPH, but failed to redox cycle in INS-1 832/13 cells and with their lysates. Although NADPH/NADP(+ )content was unaffected, NADH/NAD(+ )content decreased at 4 h post-exposure to doxorubicin, and was followed by a reduction in ATP content. Previous studies have demonstrated that doxorubicin functions as a topoisomerase II inhibitor via induction of DNA cross-linking, resulting in apoptosis. Doxorubicin induced the expression of mRNA for mdm2, cyclin G1, and fas whereas downregulating p53, and increased the melting temperature of genomic DNA, consistent with DNA damage and induction of apoptosis. Doxorubicin also induced caspase-3 and -7 activity in INS-1 832/13 cells and mouse islets; co-treatment with the pan-caspase inhibitor Z-VAD-FMK temporarily attenuated the doxorubicin-mediated loss of viability in INS-1 832/13 cells. Together, these data suggest that DNA damage, not H2O2 produced via redox cycling, is a major mechanism of doxorubicin toxicity in pancreatic β-cells.

Metformin Mitigates Fibrosis and Glucose Intolerance Induced by Doxorubicin in Subcutaneous Adipose Tissue

“…Doxorubicin administration is an effective treatment for several types of cancer and primarily functions through the promotion of cellular apoptosis ( Rochette et al, 2015 ). However, this therapy has highly undesired side effects including, but not limited to, widely reported cardiotoxicity ( Benjamin et al, 1974 ), DX also disrupts glucose and lipid metabolism and affects whole-body homeostasis ( Biondo et al, 2016 ; De Lima Junior et al, 2016 ; Heart et al, 2016 ). We demonstrated that doxorubicin treatment caused a reduction in glucose uptake after insulin stimulation and caused marked fibrosis in SAT.…”

Doxorubicin persistently rewires cardiac circadian homeostasis in mice

“…Some recent in vivo and in vitro studies observed decreased SIRT1 (Wang et al 2017;Zhu et al 2017) and SIRT3 (Cheung et al 2015;Pillai et al 2016) mRNA-expression and protein levels after DOX administration. Additionally, the metabolic shifts resultant from cardiac-DOX exposure have also shown to alter mitochondrial pathways for ATP production that could ultimately result in dysregulated NAD + /NADH ratios and NAD + levels, important linkers with the circadian regulation (Heart et al 2016;Wang et al 2014).…”

Switchable conformational changes of DNA nanogel shells containing disulfide–DNA hybrids for controlled drug release and efficient anticancer action

“…This mechanism can be enhanced by redox cycling and production of H 2 O 2 . 51 The results are presented in Fig. 7.…”