Jitka Stankova1, Jijun Shang, Rima Rozen. 1. Departments of Human Genetics, Pediatrics and Biology, Research Institute, McGill University-Montreal Children's Hospital, 4060 Saint Catherine Street West, Montreal, Quebec, Canada H3Z 2Z3.
Abstract
PURPOSE: Many cancer lines are methionine dependent and decrease proliferation when methionine supply is limited. Methylenetetrahydrofolate reductase (MTHFR) generates the folate derivative for homocysteine remethylation to methionine. We investigated the effect of antisense-mediated inhibition of MTHFR on survival of human cancer cells. EXPERIMENTAL DESIGN: We examined the in vitro and in vivo anticancer effects of a combination of MTHFR antisense and standard cytotoxic drugs. RESULTS: Specific antisense against MTHFR (EX5) showed significant inhibitory effects on growth of human colon, lung, breast, prostate, and neuroblastoma tumor cells in vitro compared with that of the control oligonucleotide. Cytotoxic drugs (5-fluorouracil, cisplatin, or paclitaxel) potentiated the effect of EX5. In vivo, antisense alone or in combination with cytotoxic drugs inhibited the growth of human colon and lung carcinoma xenografts. In comparison with control oligonucleotide, treatment with EX5 inhibited growth of colon tumors and lung tumors by 60% and 45%, respectively. EX5 with 5-fluorouracil decreased growth of colon tumors by an additional 30% compared with EX5 alone, and EX5 with cisplatin decreased growth of lung tumors by an additional 40% compared with cisplatin alone. Growth inhibition by EX5 was associated with decreased amounts of MTHFR protein and with increased amounts of an apoptosis marker. CONCLUSIONS: Our results confirm that MTHFR inhibition decreases tumor growth and suggest that inhibition of MTHFR by antisense or small molecules may be a novel anticancer approach.
PURPOSE: Many cancer lines are methionine dependent and decrease proliferation when methionine supply is limited. Methylenetetrahydrofolate reductase (MTHFR) generates the folate derivative for homocysteine remethylation to methionine. We investigated the effect of antisense-mediated inhibition of MTHFR on survival of humancancer cells. EXPERIMENTAL DESIGN: We examined the in vitro and in vivo anticancer effects of a combination of MTHFR antisense and standard cytotoxic drugs. RESULTS: Specific antisense against MTHFR (EX5) showed significant inhibitory effects on growth of human colon, lung, breast, prostate, and neuroblastoma tumor cells in vitro compared with that of the control oligonucleotide. Cytotoxic drugs (5-fluorouracil, cisplatin, or paclitaxel) potentiated the effect of EX5. In vivo, antisense alone or in combination with cytotoxic drugs inhibited the growth of humancolon and lung carcinoma xenografts. In comparison with control oligonucleotide, treatment with EX5 inhibited growth of colon tumors and lung tumors by 60% and 45%, respectively. EX5 with 5-fluorouracil decreased growth of colon tumors by an additional 30% compared with EX5 alone, and EX5 with cisplatin decreased growth of lung tumors by an additional 40% compared with cisplatin alone. Growth inhibition by EX5 was associated with decreased amounts of MTHFR protein and with increased amounts of an apoptosis marker. CONCLUSIONS: Our results confirm that MTHFR inhibition decreases tumor growth and suggest that inhibition of MTHFR by antisense or small molecules may be a novel anticancer approach.
Authors: Kathryn L Terry; Shelley S Tworoger; Ellen L Goode; Margaret A Gates; Linda Titus-Ernstoff; Linda E Kelemen; Thomas A Sellers; Susan E Hankinson; Daniel W Cramer Journal: Gynecol Oncol Date: 2010-11 Impact factor: 5.482
Authors: Gustavo A Bezerra; Alexander Holenstein; William R Foster; Bing Xie; Kevin G Hicks; Céline Bürer; Seraina Lutz; Ayan Mukherjee; Dipika Sarkar; Debomita Bhattacharya; Jared Rutter; Arindam Talukdar; Peter J Brown; Minkui Luo; Lei Shi; D Sean Froese; Wyatt W Yue Journal: Biochimie Date: 2021-01-18 Impact factor: 4.079