Mitochondrial-Targeted Curcuminoids: A Strategy to Enhance Bioavailability and Anticancer Efficacy of Curcumin

Abstract

Although the anti-cancer effects of curcumin has been shown in various cancer cell types, in vitro, pre-clinical and clinical studies showed only a limited efficacy, even at high doses. This is presumably due to low bioavailability in both plasma and tissues, particularly due to poor intracellular accumulation. A variety of methods have been developed to achieve the selective targeting of drugs to cells and mitochondrion. We used a novel approach by conjugation of curcumin to lipophilic triphenylphosphonium (TPP) cation to facilitate delivery of curcumin to mitochondria. TPP is selectively taken up by mitochondria driven by the membrane potential by several hundred folds. In this study, three mitocurcuminoids (mitocurcuminoids-1, 2, and 3) were successfully synthesized by tagging TPP to curcumin at different positions. ESI-MS analysis showed significantly higher uptake of the mitocurcuminoids in mitochondria as compared to curcumin in MCF-7 breast cancer cells. All three mitocurcuminoids exhibited significant cytotoxicity to MCF-7, MDA-MB-231, SKNSH, DU-145, and HeLa cancer cells with minimal effect on normal mammary epithelial cells (MCF-10A). The IC50 was much lower for mitocurcuminoids when compared to curcumin. The mitocurcuminoids induced significant ROS generation, a drop in ΔØm, cell-cycle arrest and apoptosis. They inhibited Akt and STAT3 phosphorylation and increased ERK phosphorylation. Mitocurcuminoids also showed upregulation of pro-apoptotic BNIP3 expression. In conclusion, the results of this study indicated that mitocurcuminoids show substantial promise for further development as a potential agent for the treatment of various cancers.

Invertible Micellar Polymer Nanoassemblies Target Bone Tumor Cells But Not Normal Osteoblast Cells

“…The results confirm earlier reports in the literature that curcumin-mediated cytotoxicity is associated with cell-cycle arrest [33,34]. The data show that IMA-delivered curcumin induces G2 arrest in osteosarcoma cells.…”

Antiproliferative effects of mitochondria-targeted cationic antioxidants and analogs: Role of mitochondrial bioenergetics and energy-sensing mechanism

“…2F), thereby implicating that the antiproliferative effects are caused independently (albeit via a similar mechanism) in cancer cells. Although previous studies have linked ROS generation to antiproliferative and cytotoxic effects of mitochondria-targeted agents (Mito-Vitamin E succinate and Mito-curcumin) in cancer cells [31,32], convincing experimental support for this proposal is lacking. Spin-trapping measurements of ROS as a minor intermediate in cancer cells treated with cationic drugs should not be interpreted as a major mechanism of cancer cell death or inhibition of cancer cell proliferation [31,32].…”

Triphenylphosphonium Cations of the Diterpenoid Isosteviol: Synthesis and Antimitotic Activity in a Sea Urchin Embryo Model

“…Specifically, this was reported for TPP derivatives of the DNA-alkylating agent chlorambucil, 39 the proapoptotic natural product curcumin, 40 and an inhibitor of DNA topoisomerases I and II, dihydrobetulinic acid. 13c, 54 The present study demonstrated that isosteviol (1) did not affect sea urchin embryo development at any stage up to a 4 μM concentration, while TPPisosteviol conjugates 14−16 and 25−27 each exhibited strong antimitotic activity.…”