ml0c00105_si_001.pdf (1.49 MB)
Designing Dihydrofolate Reductase Inhibitors as X‑ray Radiosensitizers to Reverse Radioresistance of Cervical Cancer
journal contribution
posted on 2020-06-28, 13:33 authored by Yuanwei Liang, Delong Zeng, Yuanyuan You, Bin Ma, Xiaoling Li, Tianfeng ChenX-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 greatly
promoted the therapeutic effect. This is a promising candidate for
tumor treatment that deserves further research and development. This
study clearly demonstrates that DHFR inhibitors could be developed
as promising radiosensitizers in the treatment of cervical cancer
and that further research to improve their activity and potential
in future clinical use is deserved.