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A newly synthesized nickel chelate can selectively target and overcome multidrug resistance in cancer through redox imbalance both in vivo and in vitro

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Abstract

Induction of undesired toxicity and emergence of multidrug resistance (MDR) are the major obstacles for cancer treatment. Moreover, aggressive cancers are less sensitive towards existing chemotherapeutics. Therefore, selective targeting of cancers without inducing undesired side effects and designing proper strategies to overcome MDR has utmost importance in modern chemotherapy. Previously we revealed the anticancer properties of some transition metal chelates of Schiff base, but the effectiveness of nickel complex is still unrevealed. Herein, we synthesized and characterized a Schiff base nickel chelate, nickel-(II) N-(2-hydroxyacetophenone) glycinate (NiNG), through different spectroscopic means. NiNG proves to be a broad spectrum anticancer agent with considerable efficacy to overcome MDR in cancer. Antiproliferative effects of NiNG was evaluated using drug-resistant (CEM/ADR5000; NIH-MDR-G185; EAC/Dox), drug-sensitive aggressive (Hct116; CCRF-CEM; EAC/S) and normal (NIH-3T3) cells that reveal the selective nature of NiNG towards drug resistant and sensitive cancer cells without inducing any significant toxicity in normal cells. Moreover, NiNG involves reactive oxygen species (ROS)-mediated redox imbalance for induction of caspase 3-dependent apoptosis in aggressive drug-sensitive Hct116 and drug-resistant NIH-MDR-G185 cells through disruption of mitochondrial membrane potential. Moreover, intraperitoneal (i.p.) application of NiNG at non-toxic doses caused significant increase in the life-span of Swiss albino mice bearing sensitive and doxorubicin-resistant subline of Ehrlich ascites carcinoma cells. It is noteworthy that, in vitro NiNG can only overcome P-glycoprotein-mediated MDR while in vivo NiNG can overcome MRP1-mediated MDR in cancer. Therefore, NiNG has therapeutic potential to target and overcome MDR in cancer.

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Abbreviations

Ac-DEVD-cho:

N-Ac-Asp-Glu-Val-Asp-aldehyde

ARD:

Acireductone dioxygenase

ARDS:

Adult respiratory distress syndrome

DMSO:

Dimethyl sulfoxide

DTNB:

[5,5′-Dithio-bis-(2-nitrobenzoic acid)]

MRP1:

Multidrug resistance protein 1

NAC:

N-Acetyl cysteine

Ni-SOD:

Nickel-superoxide dismutase

PEG:

Polyethylene glycol

z-VAD-fmk:

N-Benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone

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Acknowledgements

NIH-3T3 and NIH-MDR G185 cell lines were kindly provided by Dr. Michael M. Gottesman (National Cancer Institute, Bethesda, MD). CCRF-CEM and CEM/ADR5000 cell lines were kindly provided by Professor Thomas Efferth, University of Mainz, Germany. 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.

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  1. Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, 700 026, India

    Kaushik Banerjee & Soumitra Kumar Choudhuri

  2. Department of Chemistry, Ramakrishna Mission Residential College, Kolkata, India

    Manas Kumar Biswas

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  1. Kaushik Banerjee
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Correspondence to Soumitra Kumar Choudhuri.

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Banerjee, K., Biswas, M.K. & Choudhuri, S.K. A newly synthesized nickel chelate can selectively target and overcome multidrug resistance in cancer through redox imbalance both in vivo and in vitro. J Biol Inorg Chem 22, 1223–1249 (2017). https://doi.org/10.1007/s00775-017-1498-4

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