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.

Keywords: fluorouracil; irinotecan; low dose; oxaliplatin; proliferation; stroma.

Figure 1

(A) Protein levels of IGF-1R in WiDr and SW620 cells, as detected by western blot analysis. (B) Western blot analysis of HIF-1α protein levels in nuclear fractions of colon cancer cell lines (WiDr and SW620) and human microvascular endothelial cells (HMEC-1) in response to IGF-1 (13 nM), insulin (10 nM) or CoCl₂ (100 μM). Protein loading, 40 μg/well; HIF-1α band detected at ~120 kDa. Lane 1, untreated (negative control); 2, IGF-1; 3, insulin; and 4, CoCl₂ (positive control). (C) Cell-based ELISA of HIF-1α protein levels in total protein fraction in response to IGF-1 and insulin. Column 1, untreated (negative control); 2, IGF-1; 3, insulin; and 4, CoCl₂ (positive control). HIF-1α levels were standardized to untreated cells (100%). *P=0.031. IGF-1R, insulin-like growth factor-1 receptor; HIF-1α, hypoxia-inducible factor-1α; ELISA, enzyme-linked immunosorbent assay; HMEC-1, human microvascular endothelial cells.