title: Synergistic effect of allyl isothiocyanate (AITC) on cisplatin efficacy in vitro and in vivo.
abstract: Although in vitro studies have shown that isothiocyanates (ITCs) can synergistically sensitize cancer cells to cisplatin treatment, the underlying mechanisms have not been well defined, and there are no in vivo demonstrations of this synergy. Here, we report the in vitro and in vivo data for the combination of allyl isothiocyanate (AITC), one of the most common naturally occurring ITCs, with cisplatin. Our study revealed that cisplatin and AITC combination synergistically inhibits cancer cell growth and colony formation, and enhances apoptosis in association with the downregulation of antiapoptotic proteins Bcl-2 and survivin. Importantly, the in vivo combination treatment suppresses human tumor growth in animal models without observable increases in toxicity (body weight loss) in comparison with single agent treatment. Furthermore, our data revealed that addition of AITC to cisplatin treatment changes the profile of G2/M arrest (e.g. increase in M phase cell number) and significantly extends the duration of G2/M arrest in comparison with cisplatin treatment alone. To explore the underlying mechanism, we found that AITC treatment rapidly depletes b-tubulin. Combination of AITC and cisplatin inhibits the expression of G2/M checkpoint-relevant proteins including CDC2, cyclin B1 and CDC25. Together, our findings reveal a novel mechanism for AITC enhancing cisplatin efficacy and provides the first in vivo evidence to support ITCs as potential candidates for developing new regimens to overcome platinum resistance.
authors.affiliation: Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute Buffalo, New York 14263, USA ; Canget BioTekpharma LLC Buffalo, New York 14203, USA ; Department of Pharmacology, School of Pharmacy, Nantong University Nantong, Jiangsu Province, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Ling
authors.affiliation: Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute Buffalo, New York 14263, USA.
authors.forename: David
authors.initials: D
authors.lastname: Westover
authors.affiliation: Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute Buffalo, New York 14263, USA ; FC was a Roswell Summer student then and XH was a PhD student from Sichuan University trained in the FL lab then.
authors.forename: Felicia
authors.initials: F
authors.lastname: Cao
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute Buffalo, New York 14263, USA.
authors.forename: Shousong
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute Buffalo, New York 14263, USA ; FC was a Roswell Summer student then and XH was a PhD student from Sichuan University trained in the FL lab then.
authors.forename: Xiang
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute Buffalo, New York 14263, USA.
authors.forename: Hak-Ryul
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Chemoprevention, Roswell Park Cancer Institute Buffalo, New York 14263, USA.
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Denver, Colorado 80045 USA.
authors.forename: Daniel Cf
authors.initials: DC
authors.lastname: Chan
authors.affiliation: Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute Buffalo, New York 14263, USA.
authors.forename: Fengzhi
authors.initials: F
authors.lastname: Li
keywords: AITC; Bcl-2; Cisplatin; cancer cells; combination index (CI); human tumor mouse model; microtubule; survivin