A novel tin based hydroxamic acid complex induces apoptosis through redox imbalance and targets Stat3/JNK1/MMP axis to overcome drug resistance in cancer

Abstract

Undesired toxicity and emergence of multidrug resistance (MDR) are the major impediments to the successful application of organotin-based compounds against cancer. Since oxalyl-bis(N-phenyl)hydroxamic acid (OBPHA) exerts significant efficacy against cancer, we believe that derivatives of OBPHA including organotin molecule can show a promising effect against cancer. Herein, we have selected three previously characterized OBPHA derivatives viz., succinyl-bis(N-phenyl)hydroxamic acid (SBPHA), diphenyl-tin succinyl-bis(N-phenyl)hydroxamic acid (Sn-SBPHA), malonyl-bis(N-phenyl)hydroxamic acid (MBPHA) and evaluated their antiproliferative efficacy against both drug-resistant (CEM/ADR5000; EAC/Dox) and sensitive (CCRF-CEM; HeLa; EAC/S) cancers. Data revealed that Sn-SBPHA selectively targets drug-resistant and sensitive cancers without inducing any significant toxicity to normal cells (Chang Liver). Moreover, shortening of the backbone of SBPHA enhances the efficacy of the newly formed molecule MBPHA by targeting only drug-sensitive cancers. Sn-SBPHA induces caspase3-dependent apoptosis through redox-imbalance in both drug-resistant and sensitive cancer. Sn-SBPHA also reduced the activation and expression of both MMP2 and MMP9 without altering the expression status of TIMP1 and TIMP2 in drug-resistant cancer. In addition, Sn-SBPHA reduced the activation of both STAT3 and JNK1, the transcriptional modulator of MMPs, in a redox-dependent manner in CEM/ADR5000 cells. Thus, Sn-SBPHA targets MMPs by modulating STAT3 and JNK1 in a redox-dependent manner. However, MBPHA and SBPHA fail to target drug resistance and both drug-resistant and sensitive cancer respectively. Furthermore, Sn-SBPHA significantly increases the lifespan of doxorubicin-resistant and sensitive Ehrlich Ascites Carcinoma-bearing mice without inducing any significant systemic toxicity. Therefore, Sn-SBPHA has the therapeutic potential to target and overcome MDR in cancer.

Keywords:

• Apoptosis
• reactive oxygen species
• STAT3/JNK1/Matrix metalloproteinase
• hydroxamic acid
• multidrug resistance

Acknowledgment

CEM/ADR5000 and CCRF-CEM cell lines were kindly provided by Professor Thomas Efferth, University of Mainz, Germany. We thank Shayanki Lahiri, Dept. of Computational Medicine and Bioinformatics, University of Michigan Medical School, for her assistance with editing of the manuscript. This investigation received financial support from the Indian Council of Medical Research (ICMR), New Delhi, No. 74/10/2014-PERS. (EMS). The funder had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.