journal contribution
posted on 2023-04-04, 15:23 authored by Xing Wang, Natasha Raman, Ghali Lemtiri-Chlieh, Jinhee Chang, Shreya Jagtap, Dipanwita Dutta Chowdhury, Matthew Ballew, Francesca Anna Carrieri, Triet Nguyen, Katriana Nugent, Travis Peck, Michelle S. Levine, Aaron Chan, Christine Lam, Reem Malek, Tung Hoang, Ryan Phillips, ZhuoAn Cheng, Kekoa Taparra, Nick Connis, Christine L. Hann, Andrew Holland, Phuoc T. Tran, Audrey Lafargue, Hailun Wang Figure S1 shows basal centrosome amplification in cell lines. Figure S2 shows the effect of GF on cell viability. Figure S3 shows HSET expression in cell lines. Figure S4 shows the effect of GF on clonogenic potential after RT. Figure S5 shows the induction of micronuclei after GF and/or RT. Figure S6 shows the expression of IFN-β after GF and/or RT.
Funding
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...Prostate Cancer Foundation (PCF)
U.S. Department of Defense (DOD)
Uniting Against Lung Cancer
Johns Hopkins and Allegheny Health
Anonymous donor
Radiological Society of North America (RSNA)
History
ARTICLE ABSTRACT
Extra copies of centrosomes are frequently observed in cancer cells. To survive and proliferate, cancer cells have developed strategies to cluster extra-centrosomes to form bipolar mitotic spindles. The aim of this study was to investigate whether centrosome clustering (CC) inhibition (CCi) would preferentially radiosensitize non–small cell lung cancer (NSCLC). Griseofulvin (GF; FDA-approved treatment) inhibits CC, and combined with radiation treatment (RT), resulted in a significant increase in the number of NSCLC cells with multipolar spindles, and decreased cell viability and colony formation ability in vitro. In vivo, GF treatment was well tolerated by mice, and the combined therapy of GF and radiation treatment resulted in a significant tumor growth delay. Both GF and radiation treatment also induced the generation of micronuclei (MN) in vitro and in vivo and activated cyclic GMP-AMP synthase (cGAS) in NSCLC cells. A significant increase in downstream cGAS-STING pathway activation was seen after combination treatment in A549 radioresistant cells that was dependent on cGAS. In conclusion, GF increased radiation treatment efficacy in lung cancer preclinical models in vitro and in vivo. This effect may be associated with the generation of MN and the activation of cGAS. These data suggest that the combination therapy of CCi, radiation treatment, and immunotherapy could be a promising strategy to treat NSCLC.
