Abstract 1488: Altered skeletal muscle mitochondrial function and redox biology with chemotherapy and exercise in a colorectal cancer mouse model

Abstract

Abstract Background: Chemotherapy improves outcomes for patients with gastrointestinal cancer, but carries associated morbidity. Platinum-based chemotherapy adversely impacts fitness, invivo mitochondrial function, and cellular redox status in humans, however the mechanisms are poorly understood. Exercise interventions mitigate against this, but interactions between the effect of the cancer, chemotherapy, and exercise intervention are poorly understood. Using a colorectal cancer (CRC) mouse model we investigated changes in skeletal muscle oxidative phosphorylation (OxPhos) capacity and redox biology with chemotherapy and exercise. Method: SCID mice (n=48) were randomized to laparotomy with (Ca) or without (NCa) orthotopic caecal injection of DLD-1 CRC cells. CRC established over 8 weeks then mice were randomized to 1) 3 cycles of intra-peritoneal (IP) chemotherapy (Chemo; 5FU 5mg/kg, Oxaliplatin 10mg/kg and Leucovorin 90mg/kg) followed by interval exercise-training 2) Chemo and no exercise 3) IP saline sham (Sal) with exercise or 4) Sal with no exercise. Blood was collected pre and post-Chemo and at death (post-exercise), and markers of oxidative stress measured. Soleus muscle mitochondrial function was analyzed using high-resolution respirometry. Measurements included maximum OxPhos capacity (PI+II+β), Complex I and II capacities and the ratio of octanoyl-carnitine to pyruvate-supported respiration (FAO). Histopathological caecal examination was undertaken to determine cancer response. Results: Chemotherapy alone resulted in 37% lower OxPhos capacities in sham mice (p=0.011), whilst FAO was 40% lower (p=0.004). Cancer alone resulted in 38% lower OxPhos capacities (p=0.012). In combination with cancer, chemotherapy resulted in OxPhos capacities that were 42% lower than in mice with cancer but no chemotherapy (p=0.007), along with 51% lower Complex I (p<0.001) and 42% lower Complex II (p=0.007) capacities. In sham mice (NCaSal), exercise resulted in 33% greater Complex II activities (p=0.042), but exercise did not alter mitochondrial function in any other group. Total plasma protein content (TPPC) increased with time in the CaSal (+32%) and the NCaSal mice (+23%), whilst it decreased with chemotherapy (CaChemo -20%, NCaChemo -10%). Oxidative stress increased with chemotherapy and exercise, however exploratory interaction analyses are ongoing. Complete histopathological response was seen in 2 of 6 CaChemoEx animals. No other complete response was seen. Conclusion: Chemotherapy and cancer alone were associated with a loss of oxidative capacity, with a greater reduction when combined. Chemotherapy alone and with cancer caused a shift away from FAO and reduction in TPPC. Though we demonstrated an exercise effect in sham mice, exercise did not increase OxPhos capacity, nor did it ameliorate the effects of cancer and chemotherapy. A more intense exercise intervention may be required. Citation Format: Malcolm Andrew West, Alexandrina Roman, Ronan Astin, Sian Pugh, Bernadette Fernandez, Annette Hayden, Judith Cave, Eleanor Jaynes, John N. Primrose, Sandy Jack, Michael P. Grocott, Andrew Murray, Martin Feelisch, Alexander Mirnezami, Timothy Underwood. Altered skeletal muscle mitochondrial function and redox biology with chemotherapy and exercise in a colorectal cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1488. doi:10.1158/1538-7445.AM2017-1488