Abstract
X-ray radiotherapy has been widely used in the treatment of cervical cancer, a common gynecologic malignant tumor. However, the therapeutic efficacy tends to be indistinctive. One major reason for this is amplification of the dihydrofolate reductase (DHFR) gene, which causes an increase in DHFR activity and attenuation of the treatment effect. To solve this problem, we synthesized a series of DHFR inhibitors derived from methotrexate (MTX) analogues as radiotherapy sensitizers. Activity screening revealed that compound 2a exerted the best inhibitory effect toward DHFR activity. In combination with X-ray radiotherapy (4 Gy), 2a showed much more prominent antiproliferative activity on cervical cancer cells than 2a or X-rays alone and revealed higher selectivity and radiosensitization than MTX. In vitro experiments showed that 2a + X-rays significantly induced cell apoptosis, as revealed by the increase in the Sub-G1 population and activation of caspase 3, 8, and 9. The in vivo antitumor effect demonstrated that in the presence of X-rays, 2a effectively suppressed tumor growth and did not cause obvious side effects. In conclusion, as a DHFR inhibitor, 2a successfully reversed the radioresistance problem induced by radiotherapy and...Continue Reading
References
Jun 1, 1976·Cancer·R A LustigS Kramer
Sep 1, 1990·Somatic Cell and Molecular Genetics·P HahnW F Morgan
Oct 16, 2004·Blood·Moon-Taek ParkSu-Jae Lee
Mar 23, 2012·Nature Chemistry·E Joel LoveridgeRudolf K Allemann
Jul 16, 2013·Nature·Chen ChenKarsten Melcher
Aug 13, 2013·Brain : a Journal of Neurology·Kit-Yi LeungNicholas D E Greene
Oct 15, 2014·Malaria Journal·Karryn J GrestyNorman C Waters
Aug 10, 2016·Cancer Research·Annahita SallmyrAlan E Tomkinson
Oct 25, 2016·Cancer Letters·Don G LeeByoung S Kwon
Jan 13, 2017·Journal of the American Chemical Society·Dillon D BurnsByron W Purse
Feb 9, 2017·Journal of Medicinal Chemistry·Hui-Li NgWai-Keung Chui
Dec 20, 2017·ACS Chemical Neuroscience·Chongshan DaiXilong Xiao
Mar 1, 2018·American Journal of Physiology. Cell Physiology·Ngonidzashe B MadungweJean C Bopassa
Mar 22, 2018·BMC Cancer·Dan ShiXiaodong Liu
Mar 24, 2018·The Oncologist·Ulrike MoelleEva J Kantelhardt
Jun 6, 2018·Drug Delivery·Yuanwei LiangTianfeng Chen
Jun 11, 2018·European Journal of Medicinal Chemistry·Valeria FrancesconiMichele Tonelli
May 1, 2017·Chemical Science·Michael CammarataJennifer S Brodbelt
Jul 30, 2018·Cancer radiothérapie : journal de la Société française de radiothérapie oncologique·V ÉdelineT Vander Borght
Dec 5, 2018·Nature Medicine·Lucas D TruccoRichard Marais
Mar 8, 2019·Nature Communications·Wenting YangLi Tang
Apr 12, 2019·Chemical Reviews·Bowen YangJianlin Shi
Oct 28, 2019·Biomaterials·Hongxing LiuTianfeng Chen
Dec 27, 2019·Angewandte Chemie·Yanyu HuangTianfeng Chen
Mar 25, 2020·Science Advances·Lizhen HeTianfeng Chen