Mitocans Revisited: Mitochondrial Targeting as Efficient Anti-Cancer Therapy
Abstract
:1. Introduction
2. Targeting Mitochondrial Metabolism
2.1. Targeting Mitochondrial Electron Transport Chain Function
2.2. Targeting Tricarboxylic Acid (TCA) Cycle
2.3. Targeting Glycolysis and OXPHOS
3. Targeting Mitochondrial Redox Signalling Pathways and ROS Homeostasis
3.1. Targeting Redox-regulating Enzymes and ROS Production
3.2. Targeting Mitochondrial Apoptotic Signalling Pathways
4. Targeting Other Signalling Pathways that Affect Mitochondrial Functions
4.1. p53 Signalling Pathway
4.2. EGFR-Targeting via Mitochondria-Mediated Apoptosis
4.3. Mitochondrial Fission
4.4. Targeting Mitochondrial DNA (mtDNA)
5. Mitochondria-Specific Anti-Cancer Drug Delivery
5.1. Direct Conjugation of Mitochondria-Targeting Ligands to Drugs
5.2. Mitochondria-Targeting Ligands and Nanocarrier (Mitochondria-targeted Nanocarriers)
6. Conclusions
Funding
Conflicts of Interest
Abbreviations
MitoVES | Mitochondria-Targeted Vitamin-E Succinate |
MitoTam | Mitochondria-Targeted Tamoxifen |
MitoMet | Mitochondria-Targeted Metformin |
OXPHOS | Oxidative Phosphorylation |
NADPH | Nicotinamide Adenine Dinucleotide Phosphate |
NSCLC | Non-Small Cell Lung Cancer |
DHODH | Dihydroorotate Dehydrogenase |
VDAC | Voltage-Dependent Anion Channel |
TPGS | Tocopherol Polyethylene Glycol Succinate |
mtDNA | Mitochondrial DNA |
MTNs | Mitochondria-Targeted Nanocarriers |
CQDs | Carbon Quantum Dots |
α-TOS | α-Tocopheryl Succinate |
IDH | Isocitrate Dehydrogenase |
ETC | Electron Transport Chain |
ROS | Reactive Oxygen Species |
TPP | Triphenylphosphonium |
ATP | Adenosine Triphosphate |
PDT | Photodynamic Therapy |
TCA | Tricarboxylic Acid |
DQA | Dequalinium |
ADR | Adenocarcinoma |
LND | Lonidamine |
Dox | Doxorubicin |
SDH | Succinate Dehydrogenase |
2-DG | 2-Deoxyglucose |
HKII | Hexokinase II |
CIV | Complex IV |
CV | Complex V |
CII | Complex II |
CI | Complex I |
References
- Singh, B.; Modica-Napolitano, J.S.; Singh, K.K. Defining the Momiome: Promiscuous Information Transfer by Mobile Mitochondria and Mitochondrial Genome. Semin. Cancer Biol. 2017, 47, 1–17. [Google Scholar] [CrossRef]
- Dong, L.F.; Jiri Neuzil, J. Targeting mitochondria as an anticancer strategy. Cancer Commun. 2019, 39, 63. [Google Scholar] [CrossRef] [Green Version]
- Porporato, P.E.; Filigheddu, N.; Pedro, J.M.B.; Kroemer, G.; Galluzzi, L. Mitochondrial metabolism and cancer. Cell Res. 2018, 28, 265–280. [Google Scholar] [CrossRef]
- Wang, Y.; Xia, Y.; Lu, Z. Metabolic features of cancer cells. Cancer Commun. 2018, 38, 65. [Google Scholar] [CrossRef] [Green Version]
- Roth, K.G.; Mambetsariev, I.; Kulkarni, P.; Salgia, R. The mitochondrion as an emerging therapeutic target in cancer. Trends Mol. Med. 2019, 26, 119–134. [Google Scholar] [CrossRef]
- Khutornenko, A.A.; Roudko, V.V.; Chernyak, B.V.; Vartapetian, A.B.; Chumakov, P.M.; Evstafieva, A.G. Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway. Proc. Natl. Acad. Sci. USA 2010, 107, 12828–12833. [Google Scholar] [CrossRef] [Green Version]
- Tan, A.S.; Baty, J.W.; Dong, L.F.; Bezawork-Geleta, A.; Endaya, B.; Yan, B.; Goodwin, J.; Vondrusova, M.; Bajzikova, M.; Peterka, M.; et al. Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab. 2015, 21, 81–94. [Google Scholar] [CrossRef] [Green Version]
- Dong, L.F.; Kovarova, J.; Bajzikova, M.; Bezawork-Geleta, A.; Svec, D.; Endaya, B.; Schaphibulkij, K.; Coelho, A.; Sebkova, N.; Ruzickova, A.; et al. Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells. Elife 2017, 6, e22187. [Google Scholar] [CrossRef] [Green Version]
- Bajzikova, M.; Kovarova, J.; Coelho, A.R.; Boukalova, S.; Oh, S.; Rohlenova, K.; Svec, D.; Hubackova, S.; Endaya, B.; Judasova, K.; et al. Reactivation of dihydroorotate dehydrogenase-driven pyrimidine biosynthesis restores tumor growth of respiration-deficient cancer cells. Cell Metab. 2019, 29, 399–416. [Google Scholar] [CrossRef] [Green Version]
- Neuzil, J.; Dong, L.F.; Rohlena, J.; Truksa, J.; Ralph, S.J. Classification of mitocans, anti-cancer drugs acting on mitochondria. Mitochondrion 2013, 13, 199–208. [Google Scholar] [CrossRef]
- Mani, S.; Swargiary, G.; Singh, K.K. Natural Agents Targeting Mitochondria in Cancer. Int. J. Mol. Sci. 2020, 21, E6992. [Google Scholar] [CrossRef] [PubMed]
- Cui, Q.; Wen, S.; Huang, P. Targeting cancer cell mitochondria as a therapeutic approach: Recent updates. Future Med Chem. 2017, 9, 929–949. [Google Scholar] [CrossRef] [PubMed]
- Kalyanaraman, B.; Cheng, G.; Hardy, M.; Ouari, O.; Lopez, M.; Joseph, J.; Jacek Zielonka, J.; Dwinell, M.D. A review of the basics of mitochondrial bioenergetics, metabolism, and related signaling pathways in cancer cells: Therapeutic targeting of tumor mitochondria with lipophilic cationic compounds. Redox Biol. 2018, 14, 316–327. [Google Scholar] [CrossRef] [PubMed]
- Rohlenova, K.; Schaphibulkij, K.; Stursa, J.; Bezawork-Geleta, A.; Rohlena, J.; Endaya, B.; Werner, L.; Cerny, J.; Zobalova, R.; Goodwin, J.; et al. Selective Disruption of Respiratory Supercomplexes as a New Strategy to Suppress Her2high Breast Cancer. Antiox. Redox Signal. 2017, 26, 84–103. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dong, L.F.; Jameson, V.J.A.; Tilly, D.; Prochazka, L.; Rohlena, J.; Valis, K.; Truksa, J.; Zobalova, R.; Mahdavian, E.; Kluckova, K.; et al. Mitochondrial targeting of α-tocopheryl succinate enhances its pro-apoptotic efficacy: A new paradigm of efficient anti-cancer therapy. Free Radic. Biol. Med. 2011, 50, 1546–1555. [Google Scholar] [CrossRef] [PubMed]
- Du, X.; Zhang, P.; Fu, H.; Ahsan, H.M.; Gao, J.; Chen, Q. Smart mitochondrial targeted cancer therapy: Subcellular distribution, selective TrxR2 inhibition accompany with declined antioxidant capacity. Int. J. Pharm. 2019, 555, 346–355. [Google Scholar] [CrossRef]
- Noh, I.; Lee, D.Y.; Kim, H.; Jeong, C.U.; Lee, Y.; Ahn, J.O.; Hyun, H.; Park, J.H.; Kim, Y.C. Enhanced Photodynamic Cancer Treatment by Mitochondria-Targeting and Brominated Near-Infrared Fluorophores. Adv. Sci. 2018, 5, 1700481. [Google Scholar] [CrossRef] [Green Version]
- Weinberg, S.E.; Chandel, N.S. Targeting mitochondria metabolism for cancer therapy. Nat. Chem. Biol. 2015, 11, 9–15. [Google Scholar] [CrossRef] [Green Version]
- Schieber, M.; Chandel, N.S. ROS function in redox signalling and oxidative stress. Curr. Biol. 2014, 24, R453–R462. [Google Scholar] [CrossRef] [Green Version]
- Zu, X.L.; Guppy, M. Cancer metabolism: Facts, fantasy, and fiction. Biochem. Biophys. Res. Commun. 2004, 313, 459–465. [Google Scholar] [CrossRef]
- Fan, J.; Kamphorst, J.J.; Robin, M.R.; Chung, M.K.; White, E.; Shlomi, T.; Rabinowitz, J.D. Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Mol. Syst. Biol. 2013, 9, 712. [Google Scholar] [CrossRef] [PubMed]
- Jain, R.K.; Munn, L.L.; Fukumura, D. Dissecting tumour pathophysiology using intravital microscopy. Nat. Rev. Cancer 2002, 2, 266–276. [Google Scholar] [CrossRef]
- Min, H.Y.; Jung, Y.; Park, K.H.; Lee, H.Y. Papuamine Inhibits Viability of Non-small Cell Lung Cancer Cells by Inducing Mitochondrial Dysfunction. Anticancer Res. 2020, 40, 323–333. [Google Scholar] [CrossRef] [PubMed]
- Caro, P.; Kishan, A.U.; Norberg, E.; Stanley, I.; Chapuy, B.; Ficarro, S.B.; Polak, K.; Tondera, D.; Gounarides, J.; Hong Yin, H.; et al. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell. 2012, 22, 547–560. [Google Scholar] [CrossRef] [Green Version]
- Vazquez, F.; Lim, J.H.; Chim, H.; Bhalla, K.; Girnun, G.; Pierce, K.; Clish, G.B.; Granter, S.R.; Widlund, H.R.; Bruce MSpiegelman, B.M.; et al. PGC1a expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell. 2013, 23, 287–301. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wheaton, W.W.; Weinberg, S.E.; Hamanaka, R.B.; Soberanes, S.; Sullivan, L.B.; Anso, E.; Glasauer, A.; Dufour, E.; Mutluet, G.M.; et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife 2014, 3, e02242. [Google Scholar] [CrossRef]
- Kasznicki, J.; Sliwinska, A.J. Metformin in cancer prevention and therapy. Ann. Transl. Med. 2014, 2, 57. [Google Scholar]
- Missiroli, S.; Perrone, M.; Genovese, I.; Pinton, P.; Giorgi, C. Cancer metabolism and mitochondria: Finding novel mechanisms to fight tumours. Ebiomedicine 2020, 59, 102943. [Google Scholar] [CrossRef]
- Jordan, V.C. Fourteenth Gaddum Memorial Lecture. A current view of tamoxifen for the treatment and prevention of breast cancer. Br. J. Pharmacol. 1993, 110, 507–517. [Google Scholar] [CrossRef]
- Daurio, N.A.; Tuttle, S.W.; Worth, A.J.; Song, E.Y.; Davis, J.M.; Snyder, N.W.; Blair, I.A.; Koumenis, C. AMPK Activation and Metabolic Reprogramming by Tamoxifen Through Estrogen Receptor-Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment. Cancer Res. 2016, 76, 3295–3306. [Google Scholar] [CrossRef] [Green Version]
- Lee, S.; Lee, J.S.; Seo, J.; Lee, S.H.; Kang, J.H.; Song, J.; Kim, S.Y. Targeting Mitochondrial Oxidative Phosphorylation Abrogated Irinotecan Resistance in NSCLC. Sci. Rep. 2018, 8, 15707. [Google Scholar] [CrossRef] [PubMed]
- Kurelac, I.; Abarrategi, A.; Ragazzi, M.; Iommarini, L.; Ganesh, N.U.; Snoeks, T.; Bonnet, D.; Porcelli, A.M.; Malanchi, I.; Gasparre, G. A Humanized Bone Niche Model Reveals Bone Tissue Preservation Upon Targeting Mitochondrial Complex I in Pseudo-Orthotopic Osteosarcoma. J. Clin. Med. 2019, 8, 2184. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dong, L.F.; Low, P.; Dyason, J.; Wang, X.F.; Prochazka, L.; Witting, P.K.; Freeman, R.; Swettenham, E.; Valis, K.; Liu, J.; et al. α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II. Oncogene 2008, 27, 4324–4335. [Google Scholar] [CrossRef] [Green Version]
- Neuzil, J.; Dyason, J.C.; Freeman, R.; Dong, L.F.; Prochazka, L.; Wang, X.F.; Scheffler, I.E.; Ralph, S.J. Mitocans as anti-cancer agents targeting mitochondria: Lessons from studies with vitamin E analogues, inhibitors of complex II. J. Bioenerg. Biomembr. 2007, 39, 65–72. [Google Scholar] [CrossRef]
- Min, H.Y.; Jang, H.J.; Park, K.H.; Hyun, S.Y.; Park, S.J.; Kim, J.H.; Son, J.; Kang, S.S.; Lee, H.Y. The natural compound gracillin exerts potent antitumor activity by targeting mitochondrial complex II. Cell Death Dis. 2019, 10, 810. [Google Scholar] [CrossRef] [Green Version]
- Zhang, X.; Fryknäs, M.; Hernlund, E.; Fayad, W.; Milito, A.D.; Olofsson, M.H.; Gogvadze, V.; Dang, L.; Påhlman, S.; Schughart, L.A.K.; et al. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nat. Commun. 2014, 5, 3295. [Google Scholar] [CrossRef] [Green Version]
- Škrtić, M.; Sriskanthadevan, S.; Jhas, B.; Gebbia, M.; Wang, X.; Wang, Z.; Hurren, R.; Jitkova, Y.; Gronda, M.; Maclean, N.; et al. Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell 2011, 20, 674–688. [Google Scholar] [CrossRef] [Green Version]
- Chae, Y.C.; Caino, M.C.; Lisanti, S.; Ghosh, J.C.; Dohi, T.; Danial, N.N.; Villanueva, J.; Ferrero, S.; Vaira, V.; Santambrogio, L.; et al. Control of tumor bioenergetics and survival stress signaling by mitochondrial HSP90s. Cancer Cell 2012, 22, 331–344. [Google Scholar] [CrossRef] [Green Version]
- Bikas, A.; Jensen, K.; Patel, A.; Costello, J.; Kaltsas, G.; Hoperia, V.; Wartofsky, L.; Burman, K.; Vasko, V. Mitotane induces mitochondrial membrane depolarizationand apoptosis in thyroid cancer cells. Int. J. Oncol. 2019, 55, 7–20. [Google Scholar]
- Hensley, C.T.; Wasti, A.T.; DeBerardinis, R.J. Glutamine and cancer: Cell biology, physiology, and clinical opportunities. J. Clin. Investig. 2013, 123, 3678–3684. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, J.B.; Erickson, J.W.; Fuji, R.; Ramachandran, S.; Gao, P.; Dinavahi, R.; Wilson, K.F.; Ambrosio, A.L.B.; Dias, S.M.G.; Dang, C.V.; et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 2010, 18, 207–219. [Google Scholar] [CrossRef] [Green Version]
- Le, A.; Lane, A.N.; Hamaker, M.; Bose, S.; Gouw, A.; Barbi, J.; Tsukamoto, T.; Rojas, C.J.; Slusher, B.S.; Zhang, H.; et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012, 15, 110–121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thornburg, J.M.; Nelson, K.K.; Clem, B.F.; Lane, A.N.; Arumugam, S.; Simmons, A.; Eaton, J.W.; Telang, S.; Chesney, J. Targeting aspartate aminotransferase in breast cancer. Breast Cancer Res. 2008, 10, R84. [Google Scholar] [CrossRef] [Green Version]
- Qing, G.; Li, B.; Vu, A.; Skuli, N.; Walton, Z.E.; Liu, X.; Mayes, P.A.; Wise, D.R.; Thompson, C.B.; Maris, J.M.; et al. ATF4 Regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell 2012, 22, 631–644. [Google Scholar] [CrossRef] [Green Version]
- Golub, D.; Iyengar, N.; Dogra, S.; Wong, T.; Bready, D.; Tang, K.; Modrek, A.S.; Placantonakis, D.G. Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics. Front. Oncol. 2019, 9, 417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dunbar, E.M.; Coats, B.S.; Shroads, A.L.; Langaee, T.; Lew, A.; Forder, J.R.; Shuster, J.J.; Wagner, D.A.; Stacpoole, P.W. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Invest. New Drugs. 2014, 32, 452–464. [Google Scholar] [CrossRef] [Green Version]
- Lei, Y.; Yi, Y.; Liu, Y.; Liu, X.; Keller, E.T.; Qian, C.N.; Jian Zhang, J.; Yi Lu, Y. Metformin targets multiple signaling pathways in cancer. Chin. J. Cancer 2017, 36, 17. [Google Scholar] [CrossRef] [Green Version]
- Cheng, G.; Zielonka, J.; Dranka, B.P.; McAllister, D.; Mackinnon, A.C.; Joseph, J.; Kalyanaraman, B. Mitochondria-targeted drugs synergize with 2-deoxyglucose to trigger breast cancer cell death. Cancer Res. 2012, 72, 2634–2644. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xu, Y.; Gao, W.; Zhang, Y.; Wu, S.; Liu, Y.; Deng, X.; Xie, L.; Yang, J.; Yu, H.; Su, J.; et al. ABT737 reverses cisplatin resistance by targeting glucose metabolism of human ovarian cancer cells. Int. J. Oncol. 2018, 53, 1055–1068. [Google Scholar] [CrossRef] [Green Version]
- Alasadi, A.; Chen, M.; Swapna, G.V.T.; Tao, H.; Guo, J.; Collantes, J.; Fadhil, N.; Montelione, G.T.; Jin, S. Effect of mitochondrial uncouplers niclosamide ethanolamine (NEN) and oxyclozanide on hepatic metastasis of colon cancer. Cell Death Dis. 2018, 9, 215. [Google Scholar] [CrossRef] [Green Version]
- Raut, G.K.; Chakrabarti, M.; Pamarthy, D.; Bhadra, M.P. Glucose starvation-induced oxidative stress causes mitochondrial dysfunction and apoptosis via Prohibitin 1 upregulation in human breast cancer cells. Free Radic. Biol. Med. 2019, 145, 428–441. [Google Scholar] [CrossRef]
- DeNicola, G.M.; Karreth, F.A.; Humpton, T.J.; Gopinathan, A.; Wei, C.; Frese, K.; Mangal, D.; Yu, K.H.; Yeo, C.J.; Calhoun, E.S.; et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 2011, 475, 106–109. [Google Scholar] [CrossRef]
- Gorrini, C.; Harris, I.S.; Mak, T.W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 2013, 12, 931–947. [Google Scholar] [CrossRef]
- Ippolito, L.; Giannoni, E.; Chiarugi, P.; Parri, M. Mitochondrial Redox Hubs as Promising Targets for Anticancer Therapy. Front. Oncol. 2020, 10, 256. [Google Scholar] [CrossRef] [PubMed]
- Harris, I.S.; Brugge, J.S. Cancer: The enemy of my enemy is my friend. Nature 2015, 527, 170–171. [Google Scholar] [CrossRef] [PubMed]
- Panieri, E.; Santoro, M.M. ROS homeostasis and metabolism: A dangerous liason in cancer cells. Cell Death Dis. 2016, 7, e2253. [Google Scholar] [CrossRef] [PubMed]
- Yun, J.; Mullarky, E.; Lu, C.; Bosch, K.N.; Kavalier, A.; Rivera, K.; Roper, J.; Chio, I.I.; Giannopoulou, E.G.; Rago, C.; et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 2015, 350, 1391–1396. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lambeth, J.D. NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 2004, 4, 181–189. [Google Scholar] [CrossRef]
- Kussmaul, L.; Hirst, J. The mechanism of superoxide production by NADH: Ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc. Natl. Acad. Sci. USA 2006, 103, 7607–7612. [Google Scholar] [CrossRef] [Green Version]
- Quinlan, C.L.; Orr, A.L.; Perevoshchikova, I.V.; Treberg, J.R.; Ackrell, B.A.; Brand, M.D. Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J. Biol. Chem. 2012, 287, 27255–27264. [Google Scholar] [CrossRef] [Green Version]
- Lewis, C.A.; Parker, S.J.; Fiske, B.P.; McCloskey, D.; Gui, D.Y.; Green, C.R.; Vokes, N.I.; Feist, A.M.; Heiden, M.G.V.; Metallo, C.M. Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol. Cell 2014, 55, 253–263. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ning, S.; Ma, S.; Saleh, A.Q.; Guo, L.; Zhao, Z.; Chen, Y. SHMT2 Overexpression Predicts Poor Prognosis in Intrahepatic Cholangiocarcinoma. Gastroenterol. Res. Pract. 2018, 2018, 4369253. [Google Scholar] [CrossRef] [Green Version]
- Ye, J.; Fan, J.; Venneti, S.; Wan, Y.W.; Pawel, B.R.; Zhang, J.; Finley, L.W.S.; Chao Lu, C.; Lindsten, T.; Cross, J.R.; et al. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 2014, 4, 1406–1417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nilsson, R.; Jain, M.; Madhusudhan, N.; Sheppard, N.G.; Strittmatter, L.; Kampf, C.; Huang, J.; Asplund, A.; Mootha, V.K. Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat. Commun. 2014, 5, 3128. [Google Scholar] [CrossRef] [Green Version]
- Glasauer, A.; Sena, L.A.; Diebold, L.P.; Mazar, A.P.; Chandel, N.S. Targeting SOD1 reduces experimental non-small-cell lung cancer. J. Clin. Investig. 2014, 124, 117–128. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, F.X.; Liang, J.H.; Zhang, H.; Wang, Z.H.; Wan, Q.; Tan, C.P.; Ji, L.N.; Mao, Z.W. Mitochondria-Accumulating Rhenium(I) Tricarbonyl Complexes Induce Cell Death via Irreversible Oxidative Stress and Glutathione Metabolism Disturbance. ACS Appl. Mater. Interfaces 2019, 11, 13123–13133. [Google Scholar] [CrossRef] [PubMed]
- Kim, R. Recent advances in understanding the cell death pathways activated by anticancer therapy. Cancer 2005, 103, 1551–1560. [Google Scholar] [CrossRef] [PubMed]
- Jin, Z.; El-Deiry, W.S. Overview of cell death signaling pathways. Cancer Biol. Ther. 2005, 4, 139–163. [Google Scholar] [CrossRef] [Green Version]
- Yuan, S.; Akey, C.W. Apoptosome structure, assembly, and procaspase activation. Structure 2013, 21, 501–551. [Google Scholar] [CrossRef] [Green Version]
- Ghobrial, I.M.; Witzig, T.E.; Adjei, A.A. Targeting apoptosis pathways in cancer therapy. CA Cancer J. Clin. 2005, 55, 178–194. [Google Scholar] [CrossRef]
- Juárez-Salcedo, L.M.; Desai, V.; Dalia, S. Venetoclax: Evidence to date and clinical potential. Drugs Context. 2019, 8, 212574. [Google Scholar] [CrossRef] [PubMed]
- Aghvami, M.; Ebrahimi, F.; Zarei, M.H.; Salimi, A.; Jaktaji, R.P.; Pourahmad, J. Matrine Induction of ROS Mediated Apoptosis in Human ALL B-lymphocytes Via Mitochondrial Targeting. APJCP 2018, 19, 555–560. [Google Scholar]
- Mongre, R.K.; Mishra, C.B.; Prakash, A.; Jung, S.; Lee, B.S.; Kumari, S.; Jin Hong, T.; Lee, M.S. Novel Carbazole-Piperazine Hybrid Small Molecule Induces Apoptosis by Targeting BCL-2 and Inhibits Tumor Progression in Lung Adenocarcinoma In Vitro and Xenograft Mice Model. Cancers (Basel) 2019, 11, 1245. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, B.; Chen, X.; Yang, W.; He, J.; He, K.; Xia, Z.; Zhang, J.; Xiang, G. Single-walled carbon nanohorn aggregates promotes mitochondrial dysfunction-induced apoptosis in hepatoblastoma cells by targeting SIRT3. Int. J. Oncol. 2018, 53, 1129–1137. [Google Scholar] [CrossRef]
- Engelbrecht, Z.; Meijboom, R.; Cronjé, M.J. The ability of silver(I) thiocyanate 4-methoxyphenyl phosphine to induce apoptotic cell death in esophageal cancer cells is correlated to mitochondrial perturbations. Biometals 2018, 31, 189–202. [Google Scholar] [CrossRef]
- Testa, J.R.; Bellacosa, A. Akt plays a central role in tumorigenesis. Proc. Natl. Acad. Sci. USA 2001, 98, 10983–10985. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, X.; Thakkar, H.; Tyan, F.; Gim, S.; Robinson, H.; Lee, C.; Pandey, S.K.; Nwokorie, C.; Onwudiwe, N.; Srivastava, R.K. Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer. Oncogene 2001, 20, 6073–6083. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hussain, A.R.; Ahmed, S.O.; Ahmed, M.; Khan, O.S.; AbdulMohsen, S.A.; Platanias, L.C.; Al-Kuraya, K.S.; Uddin, S. Cross-talk between NFkB and the PI3-kinase/Akt pathway can be targeted in primary effusion lymphoma (PEL) cell lines for efficient apoptosis. PLoS ONE 2012, 7, e39945. [Google Scholar] [CrossRef] [PubMed]
- Zhu, Y.; Rao, Q.; Zhang, X.; Zhou, X. Galangin induced antitumor effects in human kidney tumor cells mediated via mitochondrial mediated apoptosis, inhibition of cell migration and invasion and targeting PI3K/ AKT/mTOR signalling pathway. JBUON 2018, 23, 795–799. [Google Scholar]
- Bin, W.H.; Da, L.H.; Xue, Y.; Jing, B.W. Pterostilbene (3′,5′-dimethoxy-resveratrol) exerts potent antitumor effects in HeLa human cervical cancer cells via disruption of mitochondrial membrane potential, apoptosis induction and targeting m-TOR/PI3K/Akt signalling pathway. JBUON 2018, 23, 1384–1389. [Google Scholar]
- Huang, S.; Xie, T.; Liu, W. Icariin inhibits the growth of human cervical cancer cells by inducing apoptosis and autophagy by targeting mTOR/PI3K/AKT signalling pathway. JBUON 2019, 24, 990–996. [Google Scholar] [PubMed]
- Moulder, D.E.; Hatoum, D.; Tay, E.; Lin, Y.; McGowan, E.M. The Roles of p53 in Mitochondrial Dynamics and Cancer Metabolism: The Pendulum between Survival and Death in Breast Cancer? Cancers (Basel) 2018, 10, 189. [Google Scholar] [CrossRef] [Green Version]
- Galluzzi, L.; Bravo-San Pedro, J.M.; Kroemer, G. Ferroptosis in p53-dependent oncosuppression and organismal homeostasis. Cell Death Differ. 2015, 22, 1237–1238. [Google Scholar] [CrossRef] [PubMed]
- Gnanapradeepan, K.; Basu, S.; Barnoud, T.; Budina-Kolomets, A.; Kung, C.P.; Murphy, M.E. The p53 tumor suppressor in the control of metabolism and ferroptosis. Front. Endocrinol. 2018, 9, 124. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chipuk, J.E. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 2004, 303, 1010–1014. [Google Scholar] [CrossRef] [Green Version]
- Scott, G.K.; Yau, C.; Becker, B.C.; Khateeb, S.; Mahoney, S.; Jensen, M.B.; Hann, B.; Cowen, B.J.; Pegan, S.D.; Benz, C.C. Targeting Mitochondrial Proline Dehydrogenase with a Suicide Inhibitor to Exploit Synthetic Lethal Interactions with p53 Upregulation and Glutaminase Inhibition. Mol. Cancer Ther. 2019, 18, 1374–1385. [Google Scholar] [CrossRef] [Green Version]
- Qin, Q.P.; Wang, S.L.; Tan, M.X.; Wang, Z.F.; Luo, D.M.; Zou, B.Q.; Liu, Y.C.; Yao, P.F.; Liang, H. Novel tacrine platinum (II) complexes display high anticancer activity via inhibition of telomerase activity, dysfunction of mitochondria, and activation of the p53 signaling pathway. Eur. J. Med. Chem. 2018, 158, 106–122. [Google Scholar] [CrossRef]
- Liu, W.J.; Liu, X.J.; Xu, J.; Li, L.; Li, Y.; Zhang, S.H.; Wang, J.L.; Miao, Q.F.; Zhen, Y.S. EGFR-targeting, β-defensin-tailored fusion protein exhibits high therapeutic efficacy against EGFR-expressed human carcinoma via mitochondria-mediated apoptosis. Acta Pharmacol. Sin. 2018, 39, 1777–1786. [Google Scholar] [CrossRef] [Green Version]
- Peiris-Pagès, M.; Bonuccelli, G.; Sotgia, F.; Lisanti, M.P. Mitochondrial fission as a driver of stemness in tumor cells: mDIVI1 inhibits mitochondrial function, cell migration and cancer stem cell (CSC) signalling. Oncotarget 2018, 9, 13254–13275. [Google Scholar] [CrossRef] [Green Version]
- Li, P.; Liu, Y.; Liu, W.; Li, G.; Tang, Q.; Zhang, Q.; Leng, F.; Sheng, F.; Hu, C.; Wenjing Lai, W.; et al. IR-783 inhibits breast cancer cell proliferation and migration by inducing mitochondrial fission. Int. J. Oncol. 2019, 55, 415–424. [Google Scholar] [CrossRef]
- DeBerardinis, R.J.; Mancuso, A.; Daikhin, E.; Nissim, I.; Yudkoff, M.; Wehrli, S.; Thompson, C.B. Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl. Acad. Sci. USA 2007, 104, 19345–19350. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wallace, D.C.; Fan, W. Energetics, epigenetics, mitochondrial genetics. Mitochondrion 2010, 10, 12–31. [Google Scholar] [CrossRef] [Green Version]
- Plass, C.; Pfister, S.M.; Lindroth, A.M.; Bogatyrova, O.; Claus, R.; Lichter, P. Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nat. Rev. Genet. 2013, 14, 765–780. [Google Scholar] [CrossRef] [PubMed]
- Hsu, C.C.; Tseng, L.M.; Lee, H.C. Role of mitochondrial dysfunction in cancer progression. Exp. Biol. Med. 2016, 241, 1281–1295. [Google Scholar] [CrossRef] [Green Version]
- Guha, M.; Avadhani, N.G. Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics, genetics and epigenetics. Mitochondrion 2013, 13, 577–591. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zong, W.X.; Joshua DRabinowitz, J.D.; White, E. Mitochondria and Cancer. Mol. Cell 2016, 61, 667–676. [Google Scholar] [CrossRef] [Green Version]
- Maiuri, M.C.; Kroemer, G. Essential Role for Oxidative Phosphorylation in Cancer Progression. Cell Metab. 2015, 21, 11–12. [Google Scholar] [CrossRef] [Green Version]
- Moschoi, R.; Imbert, V.; Nebout, M.; Chiche, J.; Mary, D.; Prebet, T.; Saland, E.; Castellano, R.; Pouyet, L.; Collette, Y.; et al. Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood 2016, 128, 253–264. [Google Scholar] [CrossRef] [Green Version]
- Wang, J.; Liu, X.; Qiu, Y.; Shi, Y.; Cai, J.; Wang, B.; Wei, X.; Ke, Q.; Sui, X.; Wang, Y.; et al. Cell adhesion-mediated mitochondria transfer contributes to mesenchymal stem cell-induced chemoresistance on T cell acute lymphoblastic leukemia cells. J. Hematol. Oncol. 2018, 11, 11. [Google Scholar] [CrossRef]
- Cline, S.D. Mitochondrial DNA damage and its consequences for mitochondrial gene expression. Biochim. Biophys. Acta. 2012, 1819, 979–991. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cao, J.J.; Zheng, Y.; Wu, X.W.; Tan, P.; Chen, M.H.; Wu, N.; Ji, L.N.; Mao, Z.W. Anticancer Cyclometalated Iridium(III) Complexes with Planar Ligands: Mitochondrial DNA Damage and Metabolism Disturbance. J. Med. Chem. 2019, 62, 3311–3322. [Google Scholar] [CrossRef] [PubMed]
- Wang, F.; Ogasawara, M.A.; Huang, P. Small mitochondria-targeting molecules as anti-cancer agents. Mol. Aspects Med. 2010, 31, 75–92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Heller, A.; Brockhoff, G.; Goepferich, A. Targeting drugs to mitochondria. Eur. J. Pharm. Biopharm. 2012, 82, 1–18. [Google Scholar] [CrossRef]
- Dong, L.F.; Jameson, V.J.A.; Tilly, D.; Cerny, J.; Mahdavian, E.; Marín-Hernández, A.; Hernández-Esquivel, L.; Rodríguez-Enríquez, S.; Stursa, J.; Witting, P.K.; et al. Mitochondrial targeting of vitamin E succinate enhances its pro-apoptotic and anti-cancer activity via mitochondrial complex II. J. Biol. Chem. 2011, 286, 3717–3728. [Google Scholar] [CrossRef] [Green Version]
- Battogtokh, G.; Yong-Yeon Cho, Y.Y.; Lee, J.Y.; Lee, H.S.; Kang, H.C. Mitochondrial-targeting anticancer agent conjugates and nanocarrier systems for cancer treatment. Front. Pharmacol. 2018, 9, 922. [Google Scholar] [CrossRef] [Green Version]
- Zielonka, J.; Joseph, J.; Sikora, A.; Hardy, M.; Ouari, O.; Vasquez-Vivar, J.; Cheng, G.; Lopez, M.; Kalyanaraman, B. Mitochondria-targeted triphenylphosphonium-based compounds: Syntheses, mechanisms of action, and therapeutic and diagnostic applications. Chem. Rev. 2017, 117, 10043–10120. [Google Scholar] [CrossRef]
- Rohlena, J.; Dong, L.F.; Kluckova, K.; Zobalova, R.; Goodwin, J.; Tilly, D.; Stursa, J.; Pecinova, A.; Philimonenko, A.; Hozak, P.; et al. Mitochondrially targeted α-tocopheryl succinate is antiangiogenic: Potential benefit against tumor angiogenesis but caution against wound healing. Antiox. Redox Signal. 2011, 15, 2923–2935. [Google Scholar] [CrossRef] [Green Version]
- Prochazka, L.; Koudelka, S.; Dong, L.F.; Stursa, J.; Goodwin, J.; Neca, J.; Slavik, J.; Ciganek, M.; Masek, J.; Kluckova, K.; et al. Mitochondrial targeting overcomes ABCA1-dependent resistance of lung carcinoma to α- tocopheryl succinate. Apoptosis 2013, 18, 286–299. [Google Scholar] [CrossRef]
- Kovarova, J.; Bajzikova, M.; Vondrusova, M.; Stursa, J.; Goodwin, J.; Nguyen, M.; Zobalova, R.; Alizadeh, E.; Truksa, J.; Tomasetti, M.; et al. Mitochondrial targeting of α-tocopheryl succinate enhances its anti-mesothelioma efficacy. Redox Rep. 2014, 19, 16–25. [Google Scholar] [CrossRef] [Green Version]
- Yan, B.; Stantic, M.; Zobalova, R.; Bezawork-Galeta, A.; Stapelberg, M.; Stursa, J.; Prokopova, K.; Dong, L.F.; Neuzil, J. Mitochondrially targeted vitamin E succinate efficiently kills breast tumour-initiating cells in a complex II-dependent manner. BMC Cancer 2015, 15, 401. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Boukalova, S.; Stursa, J.; Werner, L.; Ezrova, Z.; Cerny, J.; Vanova, K.; Dong, L.F.; Pecinova, A.; Neuzil, J. Mitochondrial targeting of metformin enhances its activity against pancreatic cancer. Mol. Cancer Ther. 2016, 15, 2875–2886. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bryant, K.G.; Chae, Y.C.; Martinez, R.L.; Gordon, J.C.; Elokely, K.M.; Kossenkov, A.V.; Grant, S.; Childers, W.E.; Abou-Gharbia, M.; Altieri, D.C. A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy. Oncotarget 2017, 8, 112184–112198. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Han, M.; Vakili, M.R.; Soleymani Abyaneh, H.; Molavi, O.; Lai, R.; Lavasanifar, A. Mitochondrial delivery of doxorubicin via triphenylphosphine modification for overcoming drug resistance in MDA-MB-435/DOX cells. Mol. Pharm. 2014, 11, 2640–2649. [Google Scholar] [CrossRef]
- Gazzano, E.; Lazzarato, L.; Rolando, B.; Kopecka, J.; Guglielmo, S.; Costamagna, C.; Chegaev, K.; Riganti, C. Mitochondrial delivery of phenol substructure triggers mitochondrial depolarization and apoptosis of cancer cells. Front. Pharm. 2018, 9, 580. [Google Scholar] [CrossRef]
- Millard, M.; Gallagher, J.D.; Olenyuk, B.Z.; Neamati, N. A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers. J. Med. Chem. 2013, 56, 9170–9179. [Google Scholar] [CrossRef]
- Wu, S.; Cao, Q.; Wang, X.; Cheng, K.; Cheng, Z. Design, synthesis and biological evaluation of mitochondria targeting theranostic agents. Chem. Commun. 2014, 50, 8919–8922. [Google Scholar] [CrossRef]
- Chen, W.H.; Xu, X.D.; Luo, G.F.; Jia, H.Z.; Lei, Q.; Cheng, S.X.; Zhuo, R.X.; Zhang, X.Z. Dual-Targeting Pro-apoptotic Peptide for Programmed Cancer Cell Death via Specific Mitochondria Damage. Sci. Rep. 2013, 3, 3468. [Google Scholar] [CrossRef] [Green Version]
- Wang, H.; Xu, W. Mito-methyl coumarin, a novel mitochondria-targeted drug with great antitumor potential was synthesized. Biochem. Biophys. Res. Commun. 2017, 489, 1–7. [Google Scholar] [CrossRef]
- Kirakci, K.; Zelenka, J.; Rumlová, M.; Cvačka, J.; Ruml, T.; Lang, K. Cationic octahedral molybdenum cluster complexes functionalized with mitochondria-targeting ligands: Photodynamic anticancer and antibacterial activities. Biomater. Sci. 2019, 7, 1386–1392. [Google Scholar] [CrossRef]
- Lei, W.; Xie, J.; Hou, Y.; Jiang, G.; Zhang, H.; Wang, P.; Wang, X.; Zhang, B. Mitochondria-targeting properties and photodynamic activities of porphyrin derivatives bearing cationic pendant. J. Photochem. Photobiol. 2010, B 98, 167–171. [Google Scholar] [CrossRef]
- Sun, M.; Yang, D.; Wang, C.; Bi, H.; Zhou, Y.; Wang, X.; Xu, J.; He, F.; Gai, S.; Yang, P. AgBiS2-TPP nanocomposite for mitochondrial targeting photodynamic therapy, photothermal therapy and bio-imaging under 808 nm NIR laser irradiation. Biomater. Sci. 2019, 7, 4769–4781. [Google Scholar] [CrossRef] [PubMed]
- Lampidis, T.J.; Hasin, Y.; Weiss, M.J.; Chen, L.B. Selective killing of carcinoma cells “in vitro” by lipophilic-cationic compounds: A cellular basis. Biomed. Pharmacother. 1985, 39, 220–226. [Google Scholar] [PubMed]
- Sibrian-Vazquez, M.; Nesterova, I.V.; Jensen, T.J.; Vicente, M.G.H. Mitochondria targeting by guanidine-and biguanidine-porphyrin photosensitizers. Bioconjug. Chem. 2018, 19, 705–713. [Google Scholar] [CrossRef] [PubMed]
- Baracca, A.; Sgarbi, G.; Solaini, G.; Lenaz, G. Rhodamine 123 as a probe of mitochondrial membrane potential: Evaluation of proton flux through F0 during ATP synthesis. Biochim. Biophys. Acta 2003, 1606, 137–146. [Google Scholar] [CrossRef] [Green Version]
- Antonenko, Y.N.; Avetisyan, A.V.; Cherepanov, D.A.; Knorre, D.A.; Korshunova, G.A.; Markova, O.V.; Ojovan, S.M.; Perevoshchikova, I.V.; Pustovidko, A.V.; Rokitskaya, T.I.; et al. Derivatives of rhodamine 19 as mild mitochondria-targeted cationic uncouplers. J. Biol. Chem. 2011, 286, 17831–17840. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Antonenko, Y.N.; Avetisyan, A.V.; Bakeeva, L.E.; Chernyak, B.V.; Chertkov, V.A.; Domnina, L.V.; Ivanova, O.Y.; Izyumov, D.S.; Khailova, L.S.; Klishin, S.S.; et al. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: Synthesis and in vitro studies. Biochemistry 2008, 73, 1273–1287. [Google Scholar] [CrossRef]
- Qian, W.; Sun, D.; Zhu, R.; Du, X.; Liu, H.; Wang, S. pH-sensitive strontium carbonate nanoparticles as new anticancer vehicles for controlled etoposide release. Int. J. Nanomed. 2012, 7, 5781–5792. [Google Scholar]
- Weissig, V.; Lasch, J.; Erdos, G.; Meyer, H.W.; Rowe, T.C.; Hughes, J. DQAsomes: A novel potential drug and gene delivery system made from Dequalinium. Pharm. Res. 1998, 15, 334–337. [Google Scholar] [CrossRef]
- D’Souza, G.G.; Rammohan, R.; Cheng, S.M.; Torchilin, V.P.; Weissig, V. DQAsome-mediated delivery of plasmid DNA toward mitochondria in living cells. J. Control Release 2003, 92, 189–197. [Google Scholar] [CrossRef]
- Pajuelo, L.; Calviño, E.; Diez, J.C.; Boyano-Adánez Mdel, C.; Gil, J.; Sancho, P. Dequalinium induces apoptosis in peripheral blood mononuclear cells isolated from human chronic lymphocytic leukemia. Invest. New Drugs 2011, 29, 1156–1163. [Google Scholar] [CrossRef]
- Sancho, P.; Galeano, E.; Nieto, E.; Delgado, M.D.; García-Pérez, A.I. Dequalinium induces cell death in human leukemia cells by early mitochondrial alterations which enhance ROS production. Leuk. Res. 2007, 31, 969–978. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Zhang, X.; Zhou, M.; Nan, X.; Chen, X.; Zhang, X. Mitochondrial-targeting lonidamine-doxorubicin nanoparticles for synergistic chemotherapy to conquer drug resistance. ACS Appl. Mater. Interfaces. 2017, 9, 43498–43507. [Google Scholar] [CrossRef]
- Liu, H.N.; Guo, N.N.; Wang, T.T.; Guo, W.W.; Lin, M.T.; Huang-Fu, M.Y.; Vakili, M.R.; Xu, W.H.; Chen, J.J.; Wei, Q.C.; et al. Mitochondrial targeted doxorubicin-triphenylphosphonium delivered by hyaluronic acid modified and pH responsive nanocarriers to breast tumor: In vitro and in vivo studies. Mol. Pharm. 2018, 15, 882–891. [Google Scholar] [CrossRef]
- Zhang, C.; Liu, Z.; Zheng, Y.; Geng, Y.; Han, C.; Shi, Y.; Sun, H.; Zhang, C.; Chen, Y.; Zhang, L.; et al. Glycyrrhetinic acid functionalized graphene oxide for mitochondria targeting and cancer treatment in vivo. Small 2018, 14, 1703306. [Google Scholar] [CrossRef] [PubMed]
- Stankovich, S.; Dikin, D.A.; Dommett, G.H.; Kohlhaas, K.M.; Zimney, E.J.; Stach, E.A.; Piner, R.D.; Nguyen, S.T.; Ruoff, R.S. Graphene-based composite materials. Nature 2006, 442, 282–286. [Google Scholar] [CrossRef]
- Salvi, M.; Fiore, C.; Armanini, D.; Toninello, A. Glycyrrhetinic acid-induced permeability transition in rat liver mitochondria. Biochem. Pharmacol. 2003, 66, 2375–2379. [Google Scholar] [CrossRef]
- Lim, S.Y.; Shen, W.; Gao, Z. Carbon quantum dots and their applications. Chem. Soc. Rev. 2015, 44, 362–381. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Zhang, C.; Chen, J.; Liu, L.; Hu, M.; Li, J.; Bi, H. Trackable mitochondria-targeting nanomicellar loaded with doxorubicin for overcoming drug resistance. ACS Appl. Mater. Interfaces 2017, 9, 25152–25163. [Google Scholar] [CrossRef] [PubMed]
- Song, Y.F.; Liu, D.Z.; Cheng, Y.; Liu, M.; Ye, W.L.; Zhang, B.L.; Liu, X.Y.; Zhou, S.Y. Dual subcellular compartment delivery of doxorubicin to overcome drug resistant and enhance antitumor activity. Sci. Rep. 2015, 5, 16125. [Google Scholar] [CrossRef] [PubMed]
- Lee, J.H.; Kim, K.Y.; Jin, H.; Baek, Y.E.; Choi, Y.; Jung, S.H.; Lee, S.S.; Bae, J.; Jung, J.H. Self-Assembled Coumarin Nanoparticle in Aqueous Solution as Selective Mitochondrial-Targeting Drug Delivery System. ACS Appl. Mater. Interfaces 2018, 10, 3380–3391. [Google Scholar] [CrossRef] [PubMed]
- Yu, H.; Li, J.M.; Deng, K.; Zhou, W.; Wang, C.X.; Wang, Q.; Li, K.H.; Zhao, H.Y.; Huang, S.W. Tumor acidity activated triphenylphosphonium-based mitochondrial targeting nanocarriers for overcoming drug resistance of cancer therapy. Theranostics 2019, 9, 7033–7050. [Google Scholar] [CrossRef]
- Naz, S.; Wang, M.; Han, Y.; Hu, B.; Teng, L.; Zhou, J.; Zhang, H.; Chen, J. Enzyme-responsive mesoporous silica nanoparticles for tumor cells and mitochondria multistage-targeted drug delivery. Int. J. Nanomed. 2019, 14, 2533–2542. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yan, J.; Chen, J.; Zhang, N.; Yang, Y.; Zhu, W.; Li, L.; He, B. Mitochondria-targeted tetrahedral DNA nanostructures for doxorubicin delivery and enhancement of apoptosis. J. Mater. Chem. B 2020, 8, 492–503. [Google Scholar] [CrossRef]
Mitochondrial Function | Drugs | MECHANISM of Action | Types of Tumor | Trial Stage | References |
---|---|---|---|---|---|
ETC | Papuamine | Inhibits ATP production | Lung | NA | [23] |
Metformin | Inhibits Complex I | Colon, lung, ovary, Breast, prostate | Clinical trials | [26,27,28] | |
Tamoxifen | Inhibits Complex I | Breast | FDA-Approved | [30] | |
MitoTam | Inhibits Complex I | Breast | Clinical trials | [113] | |
α-TOS | Inhibits Complex II | Breast | Preclinical | [33,34] | |
MitoVES | Inhibits Complex II | Breast | Preclinical | [105] | |
VLX600 | Inhibits Complex IV | Colon | Preclinical | [36] | |
Tigecycline | Inhibits Complex I and IV | Leukemia | FDA-Approved | [37] | |
Gamitrinib | Inhibits ATPase activity | Prostate | Preclinical | [38] | |
TCA Cycle | AGI-5198 | Inhibits IDHs activity | Glioblastoma | Clinical trials | [12,45] |
Dichloroacetate | Inhibits IDHs activity | Brain | Clinical trials | [12,46] | |
Glycolysis and OXPHOS | 2-deoxyglucose (2-DG) | Competitor for binding hexokinase | Lung, prostate, ovary, breast | Clinical trials | [47,49] |
Metformin/2DG | Inhibits ATP production | Lung, pancreas | Clinical trials | [3,47,48] | |
ABT737/2DG | Inhibits OXPHOS | Ovary | NA | [49] | |
Signalling pathways | Venetoclax | Bcl-xL inhibitor | Leukemia, lymphoma | FDA-Approved | [16,72] |
Navitoclax | Bcl-Xl/Bcl2 inhibitor | Breast, lung, prostate, colon | Clinical trials | [10,12] | |
ECPU-0001 | Bcl2 inhibitor | Lung | Preclinical | [73] | |
Gossypol | LDHA inhibitor, NADH competitor | Breast, brain, prostate | Clinical trials | [10,28] |
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Dong, L.; Gopalan, V.; Holland, O.; Neuzil, J. Mitocans Revisited: Mitochondrial Targeting as Efficient Anti-Cancer Therapy. Int. J. Mol. Sci. 2020, 21, 7941. https://doi.org/10.3390/ijms21217941
Dong L, Gopalan V, Holland O, Neuzil J. Mitocans Revisited: Mitochondrial Targeting as Efficient Anti-Cancer Therapy. International Journal of Molecular Sciences. 2020; 21(21):7941. https://doi.org/10.3390/ijms21217941
Chicago/Turabian StyleDong, Lanfeng, Vinod Gopalan, Olivia Holland, and Jiri Neuzil. 2020. "Mitocans Revisited: Mitochondrial Targeting as Efficient Anti-Cancer Therapy" International Journal of Molecular Sciences 21, no. 21: 7941. https://doi.org/10.3390/ijms21217941