Allyl isothiocyanate induces replication-associated DNA damage response in NSCLC cells and sensitizes to ionizing radiation
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Kaushlendra Tripathi1,*, Usama K. Hussein1,2,*, Roja Anupalli1,3,*, Reagan Barnett1, Lavanya Bachaboina1, Jennifer Scalici1, Rodney P. Rocconi1, Laurie B. Owen1, Gary A. Piazza1, Komaraiah Palle1,*
1Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA
2Faculty of Science, Beni Suef University, Beni Suef, Egypt
3Department of Genetics, Osmania University, Hyderabad, India
*These authors have contributed equally to this work
Komaraiah Palle, e-mail: email@example.com
Keywords: Dietary isothiocyanates, replication stress, DNA damage response, radiosensitization, non-small cell lung cancer
Received: November 21, 2014 Accepted: January 01, 2015 Published: January 27, 2015
Allyl isothiocyanate (AITC), a constituent of many cruciferous vegetables exhibits significant anticancer activities in many cancer models. Our studies provide novel insights into AITC-induced anticancer mechanisms in human A549 and H1299 non-small cell lung cancer (NSCLC) cells. AITC exposure induced replication stress in NSCLC cells as evidenced by γH2AX and FANCD2 foci, ATM/ATR-mediated checkpoint responses and S and G2/M cell cycle arrest. Furthermore, AITC-induced FANCD2 foci displayed co-localization with BrdU foci, indicating stalled or collapsed replication forks in these cells. Although PITC (phenyl isothiocyanate) exhibited concentration-dependent cytotoxic effects, treatment was less effective compared to AITC. Previously, agents that induce cell cycle arrest in S and G2/M phases were shown to sensitize tumor cells to radiation. Similar to these observations, combination therapy involving AITC followed by radiation treatment exhibited increased DDR and cell killing in NSCLC cells compared to single agent treatment. Combination index (CI) analysis revealed synergistic effects at multiple doses of AITC and radiation, resulting in CI values of less than 0.7 at Fa of 0.5 (50% reduction in survival). Collectively, these studies identify an important anticancer mechanism displayed by AITC, and suggest that the combination of AITC and radiation could be an effective therapy for NSCLC.
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