Marginal effects of glucose, insulin and insulin-like growth factor on chemotherapy response in endothelial and colorectal cancer cells

Abstract

Resistance to chemotherapy is a major clinical issue for patients with colorectal cancer. Obesity has been associated with a poorer outcome and is a possible mechanism of resistance. The aim of the present study was to investigate the effect of obesity-related factors on the cell response to standard chemotherapy in stromal and colorectal cancer cells. Viability was measured following the treatment of colorectal cancer cell lines (WiDr and SW620) and stromal cells (human microvascular endothelial cells) in vitro with 5-fluorouracil, irinotecan and oxaliplatin under obesity-related conditions [elevated levels of insulin, insulin-like growth factor-1 (IGF-1) and glucose] and compared with non-elevated conditions. Obesity-related conditions alone increased cell viability and in selected cases, accumulation of the transcription factor, hypoxia-inducible factor-1. However, these conditions did not consistently increase resistance to the chemotherapy agents tested. The combination of IGF-1 and extremely low-dose chemotherapy significantly induced cell viability in WiDr colorectal cancer cells. These in vitro results may have clinical importance in an environment of increasing rates of obesity and colorectal cancer, and the frequent under-dosing of obese cancer patients.

Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance

“… IGF pathway member Observed or experimental change Confers resistance or increases sensitivity? Affected cancer: Drug/Treatment IGF-1R Resistance Breast ER+: Tamoxifen 22 Breast HER2+: Trastuzumab 28 Gastric: Cisplatin 84 Glioma: Radiation, 73 Temozolamide 74 Hepatocellular: Apicidin 92 HNSCC: Gefitinib 102 NSCLC: Gefitinib, 52 Erlotinib, 55 Osteosarcoma: Radiation, 108 Docetaxel, Cisplatin, 107 Doxorubicin 109 , 110 Ovarian: Cisplatin ± taxol 37 Prostate: Androgen deprivation therapy 42 Sensitivity Colorectal: Multiple 91 Gastric: Cisplatin 84 , 85 Glioma: Radiation 73 Hepatocellular: Oxaliplatin 94 HNSCC: Methotrexate, Cetuximab, 104 histone deacetylase inhibitors, Rapamycin, Gemcitabine, Radiation 105 Multiple myeloma: Bortezomib 121 NSCLC: Gefitinib 54 Ovarian: Platinum-based drugs 39 Pancreatic: Gemcitabine 95 Prostate: Androgen deprivation therapy 42 IGF-1 Resistance Colorectal: Oxaliplatin, 5-Fluorouracil, Irinotecan ...…”

“… 89 Though not always observed with increased insulin or glucose concentrations, the combination of elevated IGF-1 and low-dose chemotherapy consistently increased tumor cell survival. 88 This data provides intriguing insight into how IGF signaling may serve as a link between obesity and development of drug resistance.…”

“… 87 One study looked at the in vitro effects on CRC cells of low-dose oxaliplatin, 5-fluorouracil, or irinotecan in combination with obesity-related molecular phenomena, including elevated glucose, insulin, and IGF-1. 88 This was meant to emulate a frequent situation in which obese patients are under-dosed with chemotherapy. 89 Though not always observed with increased insulin or glucose concentrations, the combination of elevated IGF-1 and low-dose chemotherapy consistently increased tumor cell survival.…”

Cell-based assays for IGF-I bioactivity measurement: overview, limitations and current trends

“…This assay involves the metabolic reduction of resazurin (blue) to a highly fluorescent, resorufin product (pink), which is then measured sphectrophotometrically at 570 nm (Erb Ehlers, 1950;Volkova et al, 2014). This bio-reduction is believed to be carried out by mitochondrial enzymes that are responsible for the transfer of electrons from resazurin to resorufin (O'Brien et al, 2000).…”

“…The MTT assay has been recently employed to evaluate the effects of IGF-I, basic-fibroblast growth factor and neuregulin on the survival and morphogenesis on mammary epithelial and cancer cells (Accornero et al, 2012) and to measure the effect of IGF-I on the apoptosis of CHO cells (Piroozmand et al, 2013), while the MTS assay has found application in several assays to determine the effect of IGF-I on cell viability and proliferation (Hou et al, 2011;Sivaramakrishnan et al, 2013;Volkova et al, 2014;Wojtalla et al, 2012).…”