Selective induction of apoptosis in various cancer cells irrespective of drug sensitivity through a copper chelate, copper N-(2 hydroxy acetophenone) glycinate: crucial involvement of glutathione

• Published in: Biometals 2013-06, Vol.26 (3), p.517-534
• Main Authors: Chatterjee, Shilpak, Chakraborty, Paramita, Banerjee, Kaushik, Sinha, Abhinaba, Adhikary, Arghya, Das, Tanya, Choudhuri, Soumitra Kumar
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Cancer; Cell Biology; Cell Survival - drug effects; Cells; Cells, Cultured; Chelating Agents - chemistry; Chelating Agents - pharmacology; Chemotherapy; Copper; Dose-Response Relationship, Drug; Drug resistance; Drug Screening Assays, Antitumor; Glutathione - metabolism; Glycine - analogs & derivatives; Glycine - chemistry; Glycine - pharmacology; HCT116 Cells; HEK293 Cells; HeLa Cells; Humans; K562 Cells; Life Sciences; Medicine/Public Health; Mice; Microbiology; NIH 3T3 Cells; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Peroxidation; Pharmacology; Pharmacology/Toxicology; Plant Physiology; Structure-Activity Relationship
• ISSN: 0966-0844; 1572-8773
• DOI: 10.1007/s10534-013-9637-z

Drug induced toxicity and drug resistance are the major impediments to successful application of cancer chemotherapy. Therefore, selective targeting of the key biochemical events of the malignant cells may have a great therapeutic potential in specifically kill the cancer cells. We have evaluated in vitro the cytotoxic efficacy of a previously reported copper complex viz. copper N -(2-hydroxy acetophenone) glycinate (CuNG) on different drug sensitive and resistant cancer cell lines by MTT, annexin V positivity and caspase 3 activation assays. We have also investigated the underlying signalling events in CuNG mediated apoptosis of cancer cells by Western blotting technique. We have found that CuNG preferentially induces apoptosis to malignant cells irrespective of drug sensitivity and spares the normal cells. Our studies disclose that CuNG causes cellular redox imbalance in cancer cells through depletion of intracellular GSH level. CuNG mediated depletion of intracellular GSH level induces mitochondrial superoxide generation, which detaches cyto C from mitochondrial membrane through lipid peroxidation. The detached cyto C then release into the extra mitochondrial milieu in Bax mediated pathway where CuNG facilitates the binding of Bax through dissociation of hexokinase II from mitochondrial membrane. The present study opens the possibility of developing effective chemotherapeutic drugs by synthesizing numerous chemical compounds capable of targeting cellular redox environment and thus specifically kills cancer cells of broad spectrum.