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Repositioning of Difluorinated Propanediones as Inhibitors of Histone Methyltransferases and their Biological Evaluation in Human Leukemic Cell Lines

[ Vol. 18 , Issue. 13 ]

Author(s):

Tanushree Pal, Asmita Sharda, Bharat Khade, C. Sinha Ramaa* and Sanjay Gupta*   Pages 1892 - 1899 ( 8 )

Abstract:


Background: At present, ‘pharmaco-epigenomics’ constitutes the hope in cancer treatment owing to epigenetic deregulation- a reversible process and playing a role in malignancy.

Objective: Chemotherapy has many limitations like host-tissue toxicity, drug resistance. Hence, it is imperative to unearth targets to better treat cancer. Here, we intend to repurpose a set of our previously synthesized difluorinated Propanediones (PR) as Histone lysine Methyltransferase inhibitors (HMTi).

Methods: The cell lines of leukemic origin viz. histiocytic lymphoma (U937) and acute T-cell leukemia (JURKAT) were treated with PR-1 to 7 after docking studies with active pocket of HMT. The cell cycle analysis, in vitro methylation and cell proliferation assays were carried out to delineate their physiological role.

Results: A small molecule PR-4, at 1 and 10µM, has shown to alter the methylation of histone H3 and H4 in both cell lines. Also, treatment shows an increase in G2/M population and a subsequent decrease in the G0/G1 population in U937. In JURKAT, an increase in both G2/M and S phase population was observed. The sub-G1 population showed a steady rise with increase in dose and prolonged time intervals in U937 and JURKAT cell lines. In SRB assay, the PR showed a cell growth of 42.6 and 53.4% comparable to adriamycin; 44.5 and 53.2% in U937 and JURKAT, respectively. The study suggests that PR-4 could emerge as a potential HMT inhibitor.

Conclusion: The molecule PR-4 could be a lead in developing more histone lysine methyltransferases inhibitors with potential to be pro-apoptotic agents.

Keywords:

Curcumin, propanediones, histone lysine methyltransferases, leukemia, anti-cancer, lymphoma (U937).

Affiliation:

Bharati Vidyapeeth's College of Pharmacy, Department of Pharmaceutical Chemistry, Sector-8, C.B.D., Belapur, Navi Mumbai-400614, Maharashtra, Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar-410210, Navi Mumbai, Maharashtra, Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar-410210, Navi Mumbai, Maharashtra, Bharati Vidyapeeth's College of Pharmacy, Department of Pharmaceutical Chemistry, Sector-8, C.B.D., Belapur, Navi Mumbai-400614, Maharashtra, Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar-410210, Navi Mumbai, Maharashtra

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