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Organosulfur derivatives of the HDAC inhibitor valproic acid sensitize human lung cancer cell lines to apoptosis and to cisplatin cytotoxicity
Author(s) -
Tesei Anna,
Brigliadori Giovanni,
Carloni Silvia,
Fabbri Francesco,
Ulivi Paola,
Arienti Chiara,
Sparatore Anna,
Del Soldato Piero,
Pasini Alice,
Amadori Dino,
Silvestrini Rosella,
Zoli Wainer
Publication year - 2012
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24039
Subject(s) - valproic acid , cisplatin , apoptosis , pharmacology , cancer research , cytotoxicity , chemistry , organosulfur compounds , lung cancer , cancer , medicine , in vitro , biochemistry , chemotherapy , epilepsy , sulfur , organic chemistry , psychiatry
Lung cancer is the leading cause of cancer mortality worldwide and despite efforts made to improve clinical results, continuing poor survival rates indicate that novel therapeutic approaches are needed. Valproic acid (VPA), a short‐chain branched fatty acid used mainly for the treatment of epilepsy and bipolar disorder, has been shown to inhibit class I histone deacetylases (HDAC‐I), a group of enzymes involved in chromatin remodeling and which are thought to play a role in tumor development. Although evidence of VPA's therapeutic efficacy has also been observed in patients with solid tumors, the very high concentration required to induce antitumor activity limits its clinical usefulness. We used a panel of NSCLC cell lines to evaluate the activity and mechanisms of action of organosulfur valproic acid derivatives, a promising new class of compounds designed to improve the safety and efficacy of the valproic acid molecule and created by coupling it with a hydrogen sulfide (H 2 S)‐releasing moiety. Our results highlighted the increased cytotoxic activity of the novel organosulfur derivatives, ACS33 and ACS2, with respect to VPA, starting from low concentrations. In particular, ACS2 exhibited important pro‐apoptotic activity triggered by the mitochondrial pathway and also showed anti‐invasion potential. Furthermore, our in vitro results identified a highly effective combination schedule of ACS2 and cisplatin capable of inducing a synergistic interaction even when the two drugs were used at low concentrations, which could prove a valid alternative to traditional chemotherapeutic regimens used for advanced lung cancer. Further studies are needed to confirm these preliminary findings. J. Cell. Physiol. 227: 3389–3396, 2012. © 2011 Wiley Periodicals, Inc.