Title
Novel Amphiphillic G-quadruplex Binding Synthetic Derivative of TMPyP4 and its Effect on Cancer Cell Proliferation and Apoptosis Induction
Author
Ushasri Chilakamarthi, Devulapally Koteshwar, Sudhakar Jinka, Narra Vamsi Krishna, Kathyayani Sridharan, Lingamallu Giribabu, Narayana Nagesh
Year
2018
Journal
Biochemistry
Abstract
Porphyrins are well known anticancer agents due to their higher binding affinity to G-quadruplex DNA and excellent photophysical properties. Several studies carried out using TMPyP4 established it as an efficient chemotherapeutic as well as Photodynamic therapeutic (PDT) agent. But its use as a lead molecule is restricted due to its high level of binding to dsDNA, which may cause side effects to normal cells and tissues. In order to minimize its interaction with dsDNA and to enhance internalization into cells, an analogue of TMPyP4 (5Me) is synthesized. Its selectivity to G-quadruplex DNA over dsDNA is evaluated by spectroscopic methods and its role in stabilizing G-quadruplex DNA was assessed by fluorescence life time and thermal melting experiments. Biophysical studies indicated that 5Me has good interaction with G-quadruplex DNA. In vitro cytotoxicity experiments with tumor cell lines (PANC-1, B16F10, MDA MB 231) have revealed that 5Me inhibited cancer cell growth comparable to TMPyP4. MTT and apoptotic assays demonstrated the ability of 5Me to specifically affect cancer cells over normal cells. Cell cycle analysis showed that 5Me is arresting the cells at G2/M phase similar to TMPyP4. Further, 5Me is more effectively taken up by both cancer and normal cells compared to TMPyP4. In addition, we have noticed that 5Me is more efficient than TMPyP4 in inhibiting the growth of the cancer cells after irradiation with light (600-720 nm, 20 J/cm2, 50 mW/cm2). By and large, the present experimental results indicate that 5Me can be an efficient chemotherapeutic as well as PDT agent.
Instrument
J-815
Keywords
Circular dichroism, DNA structure, Ligand binding, Chemical stability, Biochemistry