Phenethyl isothiocyanate synergistically induces apoptosis with Gefitinib in non-small cell lung cancer cells via endoplasmic reticulum stress-mediated degradation of Mcl-1.

Abstract

Isothiocyanates (ITCs) are natural compounds abundant in cruciferous vegetables. Numerous studies have shown that ITCs exhibit anticancer activity by affecting multiple pathways including apoptosis and oxidative stress, and are expected to be developed into novel anticancer drugs. In our previous studies, we demonstrated that ITCs effectively inhibit the proliferation of non-small cell lung cancer (NSCLC) cells, also induce apoptosis and autophagy. In the present study, we found that phenethyl isothiocyanate (PEITC) had significant synergistic effects with epidermal growth factor receptor tyrosine kinase inhibitor Gefitinib in NSCLC cell lines NCI-H1299 and SK-MES-1; and the degradation of antiapoptotic factor myeloid cell leukemia 1 (Mcl-1) caused by PEITC treatment played key roles in the sensitivity of NSCLC cells to Gefitinib. We further illustrated that PEITC regulated the expression of Mcl-1 through protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor 2α-CHOP-Noxa pathway by a posttranscriptional modulation. Pretreatment with endoplasmic reticulum stress (ER stress) inhibitor tauroursodeoxycholic acid and knockdown of PERK expression attenuated the degradation of Mcl-1 caused by PEITC. In in vivo study, nude mice bearing NCI-H1299 xenograft were administrated with PEITC (50 mg/kg, ip) and Gefitinib (50 mg/kg, ig) for 15 days, the PEITC-Gefitinib combination treatment resulted in a significant synergistic reduction in tumor growth, and significantly induced both ER stress and Mcl-1 degradation in tumor tissues. In conclusion, we explored the prospect of PEITC in improving the efficacy of targeted drug therapy and demonstrated the synergistic effects and underlined mechanisms of PEITC combined with Gefitinib in NSCLC cells treatment. This study provided useful information for developing novel therapy strategies by combination treatment of PEITC with targeted drugs.

• Authors: Qicheng Zhang, Mengmeng Chen, Limin Cao, Yinghui Ren, Xueru Guo, Xiang Wu, Ke Xu
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 59 Issue 6 Pg. 590-603 (06 2020) ISSN: 1098-2744 [Electronic] United States
• PMID: 32189414 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Wiley Periodicals, Inc.

Chemical References

• Isothiocyanates
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Reactive Oxygen Species
• phenethyl isothiocyanate
• Gefitinib

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Proliferation
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Endoplasmic Reticulum Stress (drug effects)
• Female
• Gefitinib (administration & dosage)
• Humans
• Isothiocyanates (administration & dosage)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Oxidative Stress
• Reactive Oxygen Species (metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays