INTRODUCTIONMalignant stem cells have newly been explained as the source of various types of human cancer.
These cells are typically rare and possess properties that are distinct from most other tumor cells 1. Cancer Stem Cells (CSCs) are a population of malignant cells with tumor-initiating, self-renewal and differentiation attributes. This small subset population is considered as the leading cause of tumor initiation, promotion and recurrence in various cancers2. The existence of cancer stem cells was firstly evidenced in myeloid leukemia3. In 1994, Dick and colleagues found that only the leukemic stem cells expressing the same markers as normal adult hematopoietic stem cells (CD34+CD38?), leading to the development of hematopoietic malignancy and termed these cells as leukemia-initiating cells (LIC), leukemic stem cells (LSCs) or cancer stem cells (CSCs) LSCs are now frequently accepted as a heterogeneous cell population that such cell population possesses the ability for proliferation, differentiation and self-renewal. Conventional anticancer strategy, such as surgery, chemotherapy and radiotherapy are cytotoxic to both normal and malignant cells and elderly patients cannot tolerate such severe regimens, and patients generally face the risk of recurrence, drug resistance and metastasis. Actually, these treatments usually target at a bulk tumor populations, however, leave CSCs behind4.
Increasing evidence has demonstrated that development of CSC-selective therapies is important for improving survival outcomes5. The function of antioxidants in cells as a protective mechanism during oxidative stress and apoptotic cell death has been offered. Oxidative stress illustrates an imbalance state between the generation of Reactive oxygen species (ROS) and antioxidant defenses6. ROS are mostly removed by endogenous antioxidants such as superoxide dismutase (SOD), which converts O2 to H2O2, glutathione peroxidase (GPx) and catalase (CAT) which in turn convert H2O2 to water7. Moreover, exogenous antioxidants including ascorbic acid, ?-tocopherol, ?-carotene, vitamin A prevent excessive generation, of free radicals by combining with them. Indeed when the redox balance is disrupted, creating an oxidative stress situation 8. Treatment of some cancers depends on oxidative stress situation. Several chemotherapy drugs used in cancer therapy represent their effectiveness by the generation of reactive oxygen species (ROS) and free radicals, which are part of their metabolic activity 9.
Thiosemicarbazone based metal complexes are compounds that possess antitumor, antioxidant, antibacterial, antifungal and antiviral properties10. Antitumor activity of thiosemicarbazones is often linked to the coordination of metal ions 11. Presently, the significant known effects linked to their anticancer activity are, in order of discovery, ribonucleotide reductase inhibition, generation of reactive oxygen species (ROS), topoisomerase II inhibition, mitochondria disruption and also multidrug resistance protein (MDR1) inhibition10. Such possible medical activities are owing to the powerful chelating ability of thiosemicarbazones with biologically important metal ions including Ni, Fe, Cu and their reductive capacities Nickel(II) complexes comprising sulphur and nitrogen donor ligands are many significant, since several carbon monoxide dehydrogenases and hydrogenases comprise such nickel ion as their active site12. In the present study, the effect of anti-proliferative and oxidative stress–induced apoptosis by the nickel complex of thiosemicarbazone (4-HBTC) compound on the human KG1a leukemia stem cells was examined.