Background:
Anticancer peptides (ACPs) have received increasing attention as a promising class of novel
anticancer agents owing to its potent and rapid cytotoxic properties. In this study, we aim to investigate the effects of
cationicity and hydrophobicity in modulating the cytotoxicity of PtxC, a class of ACP from the leafy mistletoe
Phoradendron tomentosum against the MDA-MB-231 and Vero cells.
Method:
We designed a series of four PtxC analogues (PA1 – PA4) by residual substitutions with specific amino acids to
introduce the specific charge and hydrophobicity alterations to the analogues. The cytotoxicity strength of the PtxC
analogues on MDA-MB-231 and Vero cells were tested by using MTT assay at 24 hours post treatment.
Results:
PA1, PA2 and PA4 displayed marked increases in cytotoxicity against both MDA-MB-231 and Vero cells and can
be ranked in the order of PA2 > PA4 > PA1 > PtxC > PA3. Sequence-activity relationship analyses of the designed
analogues showed that an increase in the level of cationicity and hydrophobicity correlated well with the enhanced cytotoxic
activity of PtxC analogues. This was observed with PA1 (netC +8) and PA2 (netC +10) in comparison to PtxC (netC +7).
Similar finding was observed for PA4 (GRAVY +0.070) in contrast to PtxC (GRAVY -0.339). Three-dimensional
modelling predicted a double α-helix structure in PtxC class of ACP. The larger first helix in PA2 and PA4 was suggested to
be responsible for the enhanced cytotoxicity observed.
Conclusion:
The critical role of cationicity and hydrophobicity in enhancing cytotoxicity of PtxC class of ACPs were
clearly demonstrated in our study. The current findings could be extrapolated to benefit peptide design strategy in other
classes of ACPs toward the discovery of highly potent ACPs against cancer cells as potential novel therapeutic agents.
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