Pixantrone confers radiosensitization in KRAS mutated cancer cells by suppression of radiation-induced prosurvival pathways

Autor:	Pragya, Tripathi, Ravi, Soni, Antra, Vibha, Tandon
Rok vydání:	2022
Předmět:	Proto-Oncogene Proteins p21(ras) Mice Phosphatidylinositol 3-Kinases Radiation-Sensitizing Agents Lung Neoplasms Cell Line Tumor Physiology (medical) Mutation Animals Humans Isoquinolines Biochemistry
Zdroj:	Free Radical Biology and Medicine. 190:351-362
ISSN:	0891-5849
Popis:	Radioresistance towards radiation therapy has generated the need for the development of radiosensitizers as a potential drug. KRAS mutation brings radioresistance in tumor cells. The present work proves sensitization of cancer cells towards radiotherapy through inhibition of KRAS activation. Acquiring a drug repurposing approach, the in-silico screening revealed that pixantrone, an antineoplastic drug, possesses a high affinity towards KRAS G12C and G12D subtypes. The SPR study suggests that maximum affinity of pixantrone was observed with KRAS G12CWTG12D and G12S. Pixantrone potentially inhibited the KRAS activation in stable transfectants G12C and G12D cell lines and radiosensitized distinct KRAS mutant subtype cells. The combination of pixantrone with radiation causes enhanced dsDNA breaks along with enhanced ATM expression, and increased late apoptosis. The preclinical studies on NCr-fox1
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fafe3d6466ee17f288b8d03a1336ef12 https://doi.org/10.1016/j.freeradbiomed.2022.08.015 Zobrazit plný text záznamu Full Text from ScienceDirect