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.
Highlights
Curcumin has been shown to exhibit anti-inflammatory, antimutagenic, anticancer and antioxidant properties [1,2]
MCF-7 cells were treated with either curcumin (10 MDA-MB-231 IC50 (mM)) or Mitocur-1, 2, 3 (10 mM) respectively for a period of 6 h
Mitochondrially-targeted mitocurcuminoid-1, 2, and 3 were synthesized by covalently coupling curcumin to lipophilic TPP cation and structures were confirmed by electrospray ionization (ESI)-MS and HRMS
Summary
Curcumin has been shown to exhibit anti-inflammatory, antimutagenic, anticancer and antioxidant properties [1,2]. It has been well established that curcumin inhibits the proliferation and survival of almost all types of tumor cells [3]. Curcumin induces cell-cycle arrest at G1/S or G2/M phases by inhibiting the expressions of cyclin D1 or cdc2/cyclin B, respectively. The major mechanism by which curcumin induces cytotoxicity in tumor cells is by the induction of apoptosis through mitochondrial pathway involving caspase-8, BID cleavage, cytochrome c release, and activation of caspase-3. The proapoptotic members of the Bcl family, such as Bax, are activated, and antiapoptotic genes such as Bcl-XL are inhibited by curcumin [4]. The apoptosis induced by curcumin in tumor cells is mediated by multiple signaling pathways that include p53, NF-kB, Akt and JAK-STAT pathways [3]
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