Inhibition of telomerase activity and induction of apoptosis by curcurnin in K-562 cells

Telomerase, a reverse transcriptase that maintains telomere length, is highly activated in tumor cells and practically absent in somatic cells and hence considered a potential marker for tumorigenesis. A connection between telomerase activity and resistance to apoptosis has been established. Telomerase, therefore, has been proposed to represent a novel and potentially selective target for cancer therapy. Several synthetic compounds have been developed in recent years with a view to inhibit telomerase activity with telomere shortening below a critical length resulting in apoptosis. Such compounds are always highly toxic. Many plant-derived products act through the induction of apoptosis as a mechanism to suppress carcinogenesis. Curcumin, a phenolic compound isolated from the rhizome of the plant Curcuma longa Linn., has been reported to possess anti-tumor, apoptotic and anti-angiogenic properties. Apoptosis has emerged as the major mechanism by which anti-tumor agents eliminate pre-neoplastic cells or cells progressed to malignancy. The present study was undertaken to examine the mechanism of curcumin-induced apoptosis in human leukemia cell line K-562 with particular emphasis on the role of curcumin on telomerase activity. Induction of apoptosis by curcumin is initiated by the release of cytochrome c from mitochondria into the cytosol, and evidenced by the increase in DNA content in the sub-G1 region as obtained from FACS analysis. Apoptosis is mediated by the activation of caspases 3 and 8, up-regulation of the apoptotic gene bax with concomitant down-regulation of the anti-apoptotic gene bcl-2. Using TRAP assay it has been observed that curcumin inhibits telomerase activity in a dose and time-dependent manner, the inhibition being due to suppression of translocation of telomerase reverse transcriptase (TERT), a catalytic subunit, from cytosol to nucleus. Most significantly, the inhibition of telomerase activity by curcumin correlates with several parameters of apoptosis. The results suggest that telomerase status plays an important role in the induction of apoptosis in K-562 cells by curcumin. (c) 2006 Elsevier B.V. All rights reserved.