Antifungal curcumin induces reactive oxygen species and triggers an early apoptosis but prevents hyphae development by targeting the global repressorTUP1inCandida albicans

Abstract

In the present study, we have investigated the antifungal effects of a natural polyphenol, CUR (curcumin), against albicans and non-albicans species of Candida and have shown its ability to inhibit the growth of all the tested strains. The inhibitory effects of CUR were independent of the status of the multidrug efflux pump proteins belonging to either ABC transporter (ATP-binding cassette transporter) or MFS (major facilitator) superfamilies of transporters. By using a systemic murine model of infection, we established that CUR and piperine, when administered together, caused a significant fungal load reduction (1.4log10) in kidneys of Swiss mice. Additionally, CUR raised the levels of ROS (reactive oxygen species), which, as revealed by annexin V-FITC labelling, triggered early apoptosis in Candida cells. Coincident with the raised ROS levels, mRNAs of tested oxidative stress-related genes [CAP1 (Candida albicans AP-1), CaIPF7817 (putative NADH-dependent flavin oxidoreductase), SOD2 (superoxide dismutase 2), GRP2 (NADPH-dependent methyl glyoxal reductase) and CAT1 (catalase 1)] were also elevated. The growth inhibitory effects of CUR could be reversed by the addition of natural and synthetic antioxidants. Notably, independent of ROS status, polyphenol CUR prevented hyphae development in both liquid and solid hypha-inducing media by targeting the global suppressor TUP1 (thymidine uptake 1). Taken together, our results provide the first evidence that CUR acts as an antifungal agent, via generation of oxidative stress, and inhibits hyphae development by targeting TUP1.

Susceptibility of clinical isolates of Candida to photodynamic effects of curcumin

“…Some previous investigations have already suggested that CUR per se may have antifungal properties [29,30] and its combination with light has been proposed in order to improve its antifungal action [23]. The results showed that the use of CUR in association with light was able to promote a significant antifungal effect against the planktonic form of the yeasts.…”

Effects of Cinnamaldehyde, Ocimene, Camphene, Curcumin and Farnesene on <i>Candida albicans</i>

“…Cinnamaldehyde was also known to inhibit growth of various microorganisms by affecting membrane integrity, energy generation and extended-spectrum beta-lactamase (ESBL) protein dependant drug resistance [17]- [19]. Curcumin is known to induce apoptosis in eukaryotic cells and also reported to inhibit planktonic and biofilm growth of C. albicans [20] [51]. Thus membrane integrity damage and apoptosis inducing activity of cinnamaldehyde and curcumin could be associated with anti-Candida activity in our study.…”

“…Curcumin is reported to up regulate TUP1, a negative regulator of hypahe induction [20] [51]. Membrane damage reported to affect membrane functions including signaling and transport [14] [15] [19] [22]- [24].…”

“…Curcumin was included to evaluate its potential against biofilm formation as it was reported to inhibit morphogenesis in C. albicans as well as shown excellent apoptosis inducing activity [20]. We have tested efficacy of these plant molecules against planktonic growth, morphogenesis and biofilm formation (adhesion, development and maturation) of C. albicans.…”

Garcinia xanthochymus Benzophenones Promote Hyphal Apoptosis and Potentiate Activity of Fluconazole against Candida albicans Biofilms

“…The presence of TUNEL-positive cells in our assays speaks to the involvement of a caspase-like mechanism similar to that mediated by the C. albicans metacaspase Mca1 in re- sponse to oxidative stress (40)(41)(42). This metacaspase-dependent system is also activated in response to treatment with resveratrol, curcumin (43), propolis (44), amphotericin B (40), and caspofungin (26). Our results suggest that the Garcinia benzophenones in this study have the characteristics of metacaspase-dependent activators of apoptosis in C. albicans biofilms.…”