Phenethyl isothiocyanate sensitizes human cervical cancer cells to apoptosis induced by cisplatin

• Published in: Molecular nutrition & food research 2011-10, Vol.55 (10), p.1572-1581
• Main Authors: Wang, Xiantao, Govind, Sudha, Sajankila, Shyama P., Mi, Lixin, Roy, Rabindra, Chung, Fung-Lung
• Format: Article
• Language: English
• Subjects: antagonists & inhibitors; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; benzyl isothiocyanate; breast neoplasms; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Butadienes; Butadienes - pharmacology; Caspase 3; Caspase 3 - metabolism; cell growth; Cell Line, Tumor; Cisplatin; Cisplatin - pharmacology; cytotoxicity; drug effects; Drug Synergism; drug therapy; epithelial cells; ERK activation; Female; HeLa Cells; Humans; Isothiocyanates; Isothiocyanates - pharmacology; JNK Mitogen-Activated Protein Kinases; JNK Mitogen-Activated Protein Kinases - metabolism; MAP Kinase Kinase 1; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 1 - metabolism; metabolism; mitogen-activated protein kinase; NF-kappa B; NF-kappa B - metabolism; Nitriles; Nitriles - pharmacology; p38 Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases - metabolism; pathology; pharmacology; Phenethyl isothiocyanate; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-bcl-2 - metabolism; Sensitization; synergism; uterine cervical neoplasms; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - pathology; watercress
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201000560

Scope: Naturally‐occurring chemopreventive agent phenethyl isothiocyanate (PEITC), derived primarily from watercress, has been shown to inhibit cell growth and induce apoptosis in cancer cells. In this study, we examined the potential of PEITC in enhancing cisplatin‐induced apoptosis in cervical cancer cells and its mechanisms. Methods and results: HeLa cells were exposed to PEITC, cisplatin or both. Pretreatment of cells with PEITC strongly enhanced cisplatin‐induced cytotoxicity. PEITC activated the mitogen‐activated protein kinases, including c‐Jun N‐terminal kinase (JNK), extracellular signal‐related kinase (ERK), and p38. Caspase‐3 activity assay demonstrated that the synergistic induction of apoptosis was significantly attenuated by MEK1/2 inhibitor U0126, but not by JNK or p38 inhibitor, suggesting that ERK activation is responsible for the synergistic effect. We found that NF‐κB signaling pathway is not involved in the synergistic effect. Sulforaphane and benzyl isothiocyanate, two other members of the isothiocyanate family, also sensitize HeLa cells to apoptosis induced by cisplatin. Furthermore, we found that the synergistic effect was also observed in cervical cancer C33A and breast cancer MCF‐7 cells but not in normal mammary epithelial MCF‐10A cells. Finally, we demonstrated that Noxa induction was associated with apoptosis induced by PEITC plus cisplatin. Conclusion: Taken together, this study shows that PEITC can sensitize cancer cells to apoptosis induced by cisplatin and this effect is mediated through ERK activation, suggesting the potential of PEITC to be used as an adjuvant with cisplatin in combination therapeutic treatments.