Cytotoxic, Genotoxic and Senolytic Potential of Native and Micellar Curcumin

Abstract

Background: Curcumin, a natural polyphenol and the principal bioactive compound in Curcuma longa, was reported to have anti-inflammatory, anti-cancer, anti-diabetic and anti-rheumatic activity. Curcumin is not only considered for preventive, but also for therapeutic, purposes in cancer therapy, which requires a killing effect on cancer cells. A drawback, however, is the low bioavailability of curcumin due to its insolubility in water. To circumvent this limitation, curcumin was administered in different water-soluble formulations, including liposomes or embedded into nanoscaled micelles. The high uptake rate of micellar curcumin makes it attractive also for cancer therapeutic strategies. Native curcumin solubilised in organic solvent was previously shown to be cytotoxic and bears a genotoxic potential. Corresponding studies with micellar curcumin are lacking. Methods: We compared the cytotoxic and genotoxic activity of native curcumin solubilised in ethanol (Cur-E) with curcumin embedded in micells (Cur-M). We measured cell death by MTT assays, apoptosis, necrosis by flow cytometry, senolysis by MTT and C12FDG and genotoxicity by FPG-alkaline and neutral singe-cell gel electrophoresis (comet assay). Results: Using a variety of primary and established cell lines, we show that Cur-E and Cur-M reduce the viability in all cell types in the same dose range. Cur-E and Cur-M induced dose-dependently apoptosis, but did not exhibit senolytic activity. In the cytotoxic dose range, Cur-E and Cur-M were positive in the alkaline and the neutral comet assay. Genotoxic effects vanished upon removal of curcumin, indicating efficient and complete repair of DNA damage. For inducing cell death, which was measured 48 h after the onset of treatment, permanent exposure was required while 60 min pulse-treatment was ineffective. In all assays, Cur-E and Cur-M were equally active, and the concentration above which significant cytotoxic and genotoxic effects were observed was 10 µM. Micelles not containing curcumin were completely inactive. Conclusions: The data show that micellar curcumin has the same cytotoxicity and genotoxicity profile as native curcumin. The effective concentration on different cell lines, including primary cells, was far above the curcumin concentration that can be achieved systemically in vivo, which leads us to conclude that native curcumin and curcumin administered as food supplement in a micellar formulation at the ADI level are not cytotoxic/genotoxic, indicating a wide margin of safety.

Micellar Curcumin: Pharmacokinetics and Effects on Inflammation Markers and PCSK‐9 Concentrations in Healthy Subjects in a Double‐Blind, Randomized, Active‐Controlled, Crossover Trial

“…This prospective, randomized, double‐blind, active‐controlled crossover trial investigated the pharmacokinetics and effects of micellar and native curcumin on pro‐inflammatory markers and PCSK9 concentrations in healthy subjects. The results of this study show 1) the enhanced bioavailability of the micellar formulation of curcumin, which agrees with earlier findings, [ 38 , 39 , 40 , 41 , 42 , 43 ] 2) no effects on IL‐6 or TNF ‐a in an ex vivo model of LPS, 3) inconclusive effects of micellar curcumin on PCSK9 concentrations, and 4) a good safety profile for curcumin when administered three times a day for 1 week.…”

Abrogation of Cellular Senescence Induced by Temozolomide in Glioblastoma Cells: Search for Senolytics

“…Lately, a number of studies have been performed on curcumin, proving its beneficial role in brain-related diseases and cancer [ 62 , 63 , 64 , 65 ]. Studies have also been performed on curcumin as an inducer of senescence [ 66 , 67 ] and senolytic agent [ 68 ]. In the experimental setting reported here curcumin at a subtoxic dose level neither reduced the senescent population nor induced apoptosis in senescent cells.…”

“…Therefore, we do not consider curcumin as a senolytic agent in our GBM cell system. Nevertheless, curcumin might still pose a beneficial option for treatment of GBM since studies indicate that high-dose curcumin is effective alone [ 68 ] and when combined with RT and anticancer drugs [ 69 , 70 , 71 , 72 ].…”

Curcumin: A Promising Tool to Develop Preventive and Therapeutic Strategies against Non-Communicable Diseases, Still Requiring Verification by Sound Clinical Trials

“…However, great efforts have been made in recent years to improve curcumin’s bioavailability by addressing these various mechanisms. To overcome the low bioavailability of curcumin due to its insolubility in water, Beltzig et al [ 10 ] administered curcumin in different water-soluble formulations, including liposomes or embedded into nanoscaled micelles. These authors successfully demonstrate that the effective concentration on different cell lines, including primary cells, was far above the curcumin concentration that can be achieved systemically in vivo, leading the authors to conclude that native curcumin and curcumin administered as food supplement in a micellar formulation are not cytotoxic/genotoxic, indicating a wide margin of safety opening new avenues in therapeutic strategies.…”