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Novel Amphiphilic G-Quadruplex Binding Synthetic Derivative of TMPyP4 and Its Effect on Cancer Cell Proliferation and Apoptosis Induction

Author:
Chilakamarthi, Ushasri, Koteshwar, Devulapally, Jinka, Sudhakar, Vamsi Krishna, Narra, Sridharan, Kathyayani, Nagesh, Narayana, Giribabu, Lingamallu
Source:
Biochemistry 2018 v.57 no.46 pp. 6514-6527
ISSN:
1520-4995
Subject:
DNA, adverse effects, antineoplastic agents, apoptosis, binding capacity, cell cycle checkpoints, cell lines, cell proliferation, cytotoxicity, drug therapy, fluorescence, irradiation, melting, neoplasm cells, neoplasms, porphyrins, spectroscopy, tissues
Abstract:
Porphyrins are well-known anticancer agents because of their high binding affinity for G-quadruplex DNA and excellent photophysical properties. Several studies carried out using TMPyP4 established it as an efficient chemotherapeutic and a photodynamic therapeutic (PDT) agent, but its use as a lead molecule has been restricted because of its high level of binding to double-stranded DNA (dsDNA), which may have side effects on normal cells and tissues. To minimize its interaction with dsDNA and to enhance internalization into cells, an analogue of TMPyP4 (5Me) was synthesized. Its selectivity for G-quadruplex DNA over dsDNA was evaluated by spectroscopic methods, and its role in stabilizing G-quadruplex DNA was assessed by fluorescence lifetime and thermal melting experiments. Biophysical studies indicated that 5Me interacts well with G-quadruplex DNA. In vitro cytotoxicity experiments with tumor cell lines (PANC-1, B16F10, and MDA MB 231) have revealed that 5Me can inhibit the growth of cancer cells 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, like TMPyP4, induces G2/M phase cell cycle arrest. In addition, 5Me is more effectively taken up by both cancer and normal cells than 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, these experimental results indicate that 5Me can be an efficient chemotherapeutic as well as a PDT agent.
Agid:
6215856