title: 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.
authors.affiliation: Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad, A.P., India.
authors.forename: Cheruku Apoorva
authors.initials: CA
authors.lastname: Reddy
authors.affiliation: Laila Impex R&D Center, Vijayawada, A.P., India.
authors.forename: Venkateswarlu
authors.initials: V
authors.lastname: Somepalli
authors.affiliation: Laila Impex R&D Center, Vijayawada, A.P., India.
authors.forename: Trimurtulu
authors.initials: T
authors.lastname: Golakoti
authors.affiliation: Centre for Chemical Biology, Indian Institute of Chemical Technology, Hyderabad, A.P., India.
authors.forename: Anantha KoteswaraRao
authors.initials: AK
authors.lastname: Kanugula
authors.affiliation: Centre for Chemical Biology, Indian Institute of Chemical Technology, Hyderabad, A.P., India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Karnewar
authors.affiliation: National Centre for Mass Spectrometry, Indian Institute of Chemical Technology, Hyderabad, A.P., India.
authors.forename: Karthikraj
authors.initials: K
authors.lastname: Rajendiran
authors.affiliation: Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad, A.P., India.
authors.forename: Nagarjuna
authors.initials: N
authors.lastname: Vasagiri
authors.affiliation: National Centre for Mass Spectrometry, Indian Institute of Chemical Technology, Hyderabad, A.P., India.
authors.forename: Sripadi
authors.initials: S
authors.lastname: Prabhakar
authors.affiliation: Department of Radiology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, United States of America.
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
authors.affiliation: Centre for Chemical Biology, Indian Institute of Chemical Technology, Hyderabad, A.P., India.
authors.forename: Srigiridhar
authors.initials: S
authors.lastname: Kotamraju
authors.affiliation: Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad, A.P., India.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Kutala
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D001692:Biological Transport; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D003474:Curcumin / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C090121:BNIP3 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D051057:Proto-Oncogene Proteins c-akt; D003474:Curcumin