Molecular biological study for association mitochondrial DNA somatic mutation with acquired anti-cancer drug resistance in digestive system cancer

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We showed that mutations in mitochondrial DNA (mtDNA: derived from pancreatic cancer, gastric cancer and colorectal cancer cell lines) are responsible for anticancer drug tolerance(5FU, CDDP, CPT-11, Gemcitabine) in vitro and in vivo with trans-mitochondrial hybrids(cybrids) technique.We used trans-mitochondrial hybrid cells (cybrids) to reveal the role of mutations in mtDNA in the pancreatic cancer by excluding any effects of the nuclear background. Cybrids were constructed by repopulating HeLa devoid of mtDNA with mtDNA derived from enucleated the pancreatic cancer, gastric cancer and colorectal cancer cell lines sharboring mtDNA mutations. We constructed several cybrids with mutations derived from the cancer cells as well as those with wild mtDNA derived healthy individuals, and transplanted mutant and wild type cybrids into nude mice to generate tumors. We compared tumor growth and massive apoptosis of mutant cybrid tumors to wild cybrid tumors administrated of 5FU, CDDP, CPT-11, Gemcitabine. All experiments were performed in accordance with the guidelines of the Animal Use Ethics Committee of Nippon Medical School.Result:Tumors derived from mutant cybrids were more resistant than those from wild-type cybrids in suppressing tumor growth and inducing massive apoptosis when the all of anti-cancerdrugs were administered.