Abstract
Curcumin has been widely investigated for its myriad cellular effects resulting in reduced proliferation of various eukaryotic cells including cancer cells and the human malaria parasite Plasmodium falciparum. Studies with human cancer cell lines HT-29, Caco-2, and MCF-7 suggest that curcumin can bind to tubulin and induce alterations in microtubule structure. Based on this finding, we investigated whether curcumin has any effect on P. falciparum microtubules, considering that mammalian and parasite tubulin are 83% identical. IC50 of curcumin was found to be 5 µM as compared to 20 µM reported before. Immunofluorescence images of parasites treated with 5 or 20 µM curcumin showed a concentration-dependent effect on parasite microtubules resulting in diffuse staining contrasting with the discrete hemispindles and subpellicular microtubules observed in untreated parasites. The effect on P. falciparum microtubules was evident only in the second cycle for both concentrations tested. This diffuse pattern of tubulin fluorescence in curcumin treated parasites was similar to the effect of a microtubule destabilizing drug vinblastine on P. falciparum. Molecular docking predicted the binding site of curcumin at the interface of alpha and beta tubulin, similar to another destabilizing drug colchicine. Data from predicted drug binding is supported by results from drug combination assays showing antagonistic interactions between curcumin and colchicine, sharing a similar binding site, and additive/synergistic interactions of curcumin with paclitaxel and vinblastine, having different binding sites. This evidence suggests that cellular effects of curcumin are at least, in part, due to its perturbing effect on P. falciparum microtubules. The action of curcumin, both direct and indirect, on P. falciparum microtubules is discussed.
Highlights
Curcumin or diferuloylmethane is a naturally occurring phenolic derivative, experimentally proven to possess anti-malaria activity against various Plasmodium species [1,2,3]
Another study noted that curcumin interacts with the sarcoplasmic Ca+ ATPase (SERCA) of P. falciparum and suggested that this may account for its anti-malaria mechanism [5]
Previous reports have demonstrated the anti-malaria potential of curcumin with IC50 values ranging from 5 to 30 mM [1,2,42]
Summary
Curcumin or diferuloylmethane (from the root of Curcuma longa) is a naturally occurring phenolic derivative, experimentally proven to possess anti-malaria activity against various Plasmodium species [1,2,3]. Its anti-malaria activities have been partially attributed to pro-oxidant properties and the ability to inhibit histone acetyltransferases [1]. The pro-oxidant activity of curcumin is believed to be responsible for its role in immunomodulation [4]. Another study noted that curcumin interacts with the sarcoplasmic Ca+ ATPase (SERCA) of P. falciparum and suggested that this may account for its anti-malaria mechanism [5]. Recombinant P. falciparum glyoxalase (GloI) has been found to be inhibited by curcumin in vitro [6]. Curcumin appears to have several targets in the parasite that singly or collectively may be responsible for its observed antiparasitic action
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