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Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells.

ABSTRACT: The platinum compound oxaliplatin has been shown to be an effective chemotherapeutic agent for the treatment of colorectal cancer. In this study, we investigate the molecular mechanisms of action of oxaliplatin to identify means of predicting response to this agent. Exposure of colon cancer cells to oxaliplatin resulted in G2/M arrest and apoptosis. Immunofluorescent staining demonstrated that the apoptotic cascade initiated by oxaliplatin is characterised by translocation of Bax to the mitochondria and cytochrome c release into the cytosol. Oxaliplatin treatment resulted in caspase 3 activation and oxaliplatin-induced apoptosis was abrogated by inhibition of caspase activity with z-VAD-fmk, but was independent of Fas/FasL association. Targeted inactivation of Bax or p53 in HCT116 cells resulted in significantly increased resistance to oxaliplatin. However, the mutational status of p53 was unable to predict response to oxaliplatin in a panel of 30 different colorectal cancer cell lines. In contrast, the expression profile of these 30 cell lines, assessed using a 9216-sequence cDNA microarray, successfully predicted the apoptotic response to oxaliplatin. A leave-one-out cross-validation approach was used to demonstrate a significant correlation between experimentally observed and expression profile predicted apoptosis in response to clinically achievable doses of oxaliplatin (R=0.53; P=0.002). In addition, these microarray experiments identified several genes involved in control of apoptosis and DNA damage repair that were significantly correlated with response to oxaliplatin.

SUBMITTER: Arango D

PROVIDER: S-EPMC2409767 | biostudies-literature | 2004 Nov

REPOSITORIES: biostudies-literature

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Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells.

Arango D D Wilson A J AJ Shi Q Q Corner G A GA Arañes M J MJ Nicholas C C Lesser M M Mariadason J M JM Augenlicht L H LH

British journal of cancer 20041101 11

The platinum compound oxaliplatin has been shown to be an effective chemotherapeutic agent for the treatment of colorectal cancer. In this study, we investigate the molecular mechanisms of action of oxaliplatin to identify means of predicting response to this agent. Exposure of colon cancer cells to oxaliplatin resulted in G2/M arrest and apoptosis. Immunofluorescent staining demonstrated that the apoptotic cascade initiated by oxaliplatin is characterised by translocation of Bax to the mitochon ...[more]

PMID: 15545975

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Project description:The response of cancer patients to oxaliplatin combined with 5-fluorouracil (5-FU) is difficult to predict. It has been reported that carcinoma-associated fibroblasts (CAFs) could induce AKT and ERK phosphorylation, and upregulate survivin expression in colorectal cancer (CRC) cells, which could lead to oxaliplatin plus 5-FU resistance. A total of 71 patients with advanced CRC (aCRC) treated with oxaliplatin plus 5-FU were included in the present study. These patients comprised 46 chemotherapy responders and 25 non-responders. The expression levels of ?-smooth muscle actin (?-SMA), phosphorylated (p)-AKT, p-ERK and survivin were determined by immunohistochemical evaluation of paraffin-embedded samples from patients. A predictive model was established using a Probabilistic Neural Network model. The high expression of ?-SMA, p-AKT and survivin in patients with aCRC were associated with oxaliplatin plus 5-FU resistance (P<0.001, P=0.023 and P=0.001, respectively). Furthermore, patients with stage IV CRC exhibiting high expression levels of ?-SMA and survivin experienced a reduced progression-free survival time compared with patients with low expressions of ?-SMA and survivin (5.5 vs. 15.0 months; 5.5 vs. 15.0 months; P=0.005 and P=0.001, respectively). Stage IV CRC and high survivin expression predicted a reduced overall survival time compared with that for patients with stage IV CRC and low survivin expression (50.0 vs. 15.0 months; P<0.001). Patients with ?-SMA, p-AKT, p-ERK and survivin overexpression were more likely to present with intrinsic resistance to the oxaliplatin plus 5-FU regimen (the accuracies of modeling, validation and prediction were 83.7, 92.9 and 85.7%, respectively). In conclusion, the multifactorial predictive biomarker model of ?-SMA, p-AKT, p-ERK and survivin expression for patients with aCRC to predict intrinsic resistance to oxaliplatin plus 5-FU regimens is of great efficiency and accuracy. Patients with high expression of this predictive model may be intrinsically resistant to the oxaliplatin and 5-FU regimen.

Project description:BackgroundKRAS mutations are fraught with the progression of colorectal cancer and resistance to chemotherapy. There are pathways such as extracellular regulated protein kinase 1/2 (ERK1/2) and Akt downstream and farnesylation and geranylgeranylation upstream that are activated upon mutated KRAS. Previous studies have shown that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are effective to treat KRAS mutated colorectal cancer cells. Increased doses of oxaliplatin (L-OHP), a well-known alkylating chemotherapeutic drug, causes side effects such as peripheral neuropathy due to ERK1/2 activation in spinal cords. Hence, we examined the combinatorial therapeutic efficacy of statins and L-OHP to reduce colorectal cancer cell growth and abrogate neuropathy in mice.MethodsCell survival and confirmed apoptosis was assessed using WST-8 assay and Annexin V detection kit. Detection of phosphorylated and total proteins was analyzed the western blotting. Combined effect of simvastatin and L-OHP was examined the allograft mouse model and L-OHP-induced neuropathy was assessed using cold plate and von Frey filament test.ResultsIn this study, we examined the effect of combining statins with L-OHP on induction of cell death in colorectal cancer cell lines and improvement of L-OHP-induced neuropathy in vivo. We demonstrated that combined administration with statins and L-OHP significantly induced apoptosis and elevated the sensitivity of KRAS-mutated colorectal cancer cells to L-OHP. In addition, simvastatin suppressed KRAS prenylation, thereby enhancing antitumor effect of L-OHP through downregulation of survivin, XIAP, Bcl-xL, and Bcl-2, and upregulation of p53 and PUMA via inhibition of nuclear factor of κB (NF-κB) and Akt activation, and induction of c-Jun N-terminal kinase (JNK) activation in KRAS-mutated colorectal cancer cells. Moreover, simvastatin enhanced the antitumor effects of L-OHP and suppressed L-OHP-induced neuropathy via ERK1/2 activation in vivo.ConclusionTherefore, statins may be therapeutically useful as adjuvants to L-OHP in KRAS-mutated colorectal cancer and may also be useful in the treatment of L-OHP-induced neuropathy.

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Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells.

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Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells.

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