Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism |
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| Authors: | Divya Pathania Nouri Neamati |
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| Affiliation: | Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA 90089, USA |
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| Abstract: | Cancer cells are characterized by self-sufficiency in the absence of growth signals, their ability to evade apoptosis, resistance to anti-growth signals, sustained angiogenesis, uncontrolled proliferation, and invasion and metastasis. Alterations in cellular bioenergetics are an emerging hallmark of cancer. The mitochondrion is the major organelle implicated in the cellular bioenergetic and biosynthetic changes accompanying cancer. These bioenergetic modifications contribute to the invasive, metastatic and adaptive properties typical in most tumors. Moreover, mitochondrial DNA mutations complement the bioenergetic changes in cancer. Several cancer management therapies have been proposed that target tumor cell metabolism and mitochondria. Glycolytic inhibitors serve as a classical example of cancer metabolism targeting agents. Several TCA cycle and OXPHOS inhibitors are being tested for their anticancer potential. Moreover, agents targeting the PDC/PDK (pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase) interaction are being studied for reversal of Warburg effect. Targeting of the apoptotic regulatory machinery of mitochondria is another potential anticancer field in need of exploration. Additionally, oxidative phosphorylation uncouplers, potassium channel modulators, and mitochondrial redox are under investigation for their anticancer potential. To this end there is an increased demand for agents that specifically hit their target. Delocalized lipophilic cations have shown tremendous potential in delivering anticancer agents selectively to tumor cells. This review provides an overview of the potential anticancer agents that act by targeting cancer cell metabolism and mitochondria, and also brings us face to face with the emerging opportunities in cancer therapy. |
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| Keywords: | AIF, apoptosis inducing factor AVPI, alanine valine proline isoleucine BAD, Bcl-2 antagonist of cell death BAX, Bcl-2 associated protein X BAK, Bcl-2 homologous antagonist/killer BH, Bcl-2 homology domain BIR, baculovirus IAP repeat 1,3-BPG, 1,3-bisphosphoglycerate AMF, autocrine motility factor ANT, adenine nucleotide transporter ARD1, arrest-defective 1 protein BCNU, bis-chloronitrosourea 3-BrP, 3-bromopyruvate CAD, c-terminal activation domain CARD, caspase recruitment domain CBP, CREB binding protein CCCP, carbonylcyanide-3-chlorophenylhydrazone COX4/2, cyotochrome oxidase isoform2 CT, computed tomography DCA, dichloroacetate 2-DG, 2-deoxyglucose DHAP, dihydroxy acetone phosphate DIABLO, Direct Inhibitor of Apoptosis Binding protein with a Low pI DLC, delocalized lipophilic cation DNP, 2,4-dinitrophenol EGFR, epidermal growth factor receptor ERK, extracellular signal regulated kinase ETC, electron transport chain FAD, flavin adenine dinucleotide (oxidized) FADH2, flavin adenine dinucleotide (reduced) 18FBzTPP, 4-(18F-benzyl) triphenylphosphonium FCCP, p-trifluoromethoxyphenylhydrazone FDA, Food and Drug Administration 18F-FDG, 18F-deoxygluxose FH, fumarate hydratase FIH, factor inhibiting HIF-1 FNQ, furanonapthoquinone F-1,6-BP, fructose-1,6-bisphosphate F-6-P, fructose-6-phosphate GAPDH, glyceraldehyde-3-phosphate dehydrogenase GPI, glucose phosphate isomerase Glut, glucose transporter G-6-P, glucose-6-phosphate Glyc-3-P, glyceraldehydes-3-phosphate HBD, hydrogen bonding donor HBA, hydrogen bonding acceptor HDAC, histone deacetylase HIF-1, hypoxia inducible factor-1 HK, hexokinase HLRCC, hereditary leiomyomatosis/renal cell cancer PGL, hereditary paraganglioma Hsp90, heat shock protein 90 3H-TPP, 3H-tetraphenylphosphonium IAP, inhibitor of apoptosis protein IMM, inner mitochondrial membrane JNK, c-Jun N-terminal kinase LDH, lactate dehydrogenase MAPK, mitogen activated protein kinase MDR, multidrug resistance MEK, MAPK-ERK kinase M2-PK, pyruvate kinase M2 MMP, matrix metalloproteinase MOM, mitochondrial outer membrane MPP+, 1-methyl-4-phenylpyridinium cation MPT, membrane permeability transition MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 99m-Tc-MIBI, 99m-Tc-Sestamibi MTD, maximum tolerated dose mTOR, mammalian target of rapamycin NAD+, nicotinamide adenine dinucleotide (oxidized) NADH, nicotinamide adenine dinucleotide (reduced) NADPH, nicotinamide adenine dinucleotide phosphate (reduced) NCI, National Cancer Institute NFAT, nuclear factor of activated T cells NO, nitric oxide OXPHOS, oxidative phosphorylation PCD, programmed cell death PDC, pyruvate dehydrogenase complex PDT, photodynamic therapy PDK, pyruvate dehydrogenase kinase PDP, pyruvate dehydrogenase phosphatase PEP, phosphoenol pyruvate PET, positron emission tomography PHD, prolyl hydroxylase PI3K, phosphoinositide 3-kinase PFK, phosphofructokinase PFKFB, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2-PG, 2-phosphoglycerate 3-PG, 3-phosphoglcerate PGK, phosphoglycerate kinase PGM, phosphoglycerate mutase Pgp, p-glycoprotein PK, pyruvate kinase PKCδ, protein kinase C delta PS, photosensitizer PSA, prostate specific antigen PTP, permeability transition pore pVHL, von Hippel-Lindau protein ROS, reactive oxygen species SAR, structure activity relationship SCO2, synthesis of cytochrome c oxidase2 SDH, succinate dehydrogenase Smac, Second mitochondria derived activator of caspases SPECT, single photon emission computed tomography TIGAR, tp53 induced glycolysis and apoptosis regulator TCA cycle, tricarboxyclic acid cycle TNFR, tumor necrosis factor receptor TPA, triphenylarsonium TPP, triphenylphosphonium cation TRAF, TNF receptor associated family of proteins TKTL1, transketolase like enzyme1 αTOS, α-tocopheryl succinate TPI, triosephosphate isomerase Trx/TrxR, thioredoxin/thioredoxin reductase VDAC, voltage dependent anion channel XIAP, X-linked inhibitor of apoptosis protein |
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