Allyl isothiocyanate induces replication-associated DNA damage response in NSCLC cells and sensitizes to ionizing radiation.

Abstract

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.

• Authors: Kaushlendra Tripathi, Usama K Hussein, Roja Anupalli, Reagan Barnett, Lavanya Bachaboina, Jennifer Scalici, Rodney P Rocconi, Laurie B Owen, Gary A Piazza, Komaraiah Palle
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 7 Pg. 5237-52 (Mar 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25742788 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Food Preservatives
• Isothiocyanates
• Radiation-Sensitizing Agents
• allyl isothiocyanate

Topics

• Apoptosis (drug effects, radiation effects)
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (genetics, pathology, therapy)
• Cell Cycle (drug effects, radiation effects)
• Cell Movement (drug effects, radiation effects)
• Cell Proliferation (drug effects, radiation effects)
• DNA Damage (drug effects, radiation effects)
• DNA Replication (drug effects, radiation effects)
• Flow Cytometry
• Fluorescent Antibody Technique
• Food Preservatives (pharmacology)
• G2 Phase Cell Cycle Checkpoints (drug effects, radiation effects)
• Humans
• Isothiocyanates (pharmacology)
• Lung Neoplasms (genetics, pathology, therapy)
• Radiation, Ionizing
• Radiation-Sensitizing Agents (pharmacology)
• Tumor Cells, Cultured