Synergistic cancer starvation therapy via mitochondria targeting cell penetrating polypeptide

Hoyeon Nam; Yeu-Chun Kim

Journal of Industrial and Engineering Chemistry, Vol.104, 397-405, December, 2021

DOI10.1016/j.jiec.2021.08.030 Export Citation

Synergistic cancer starvation therapy via mitochondria targeting cell penetrating polypeptide

Hoyeon Nam, and Yeu-Chun Kim^†

Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

E-mail:

Aberrant cancer metabolism has been recognized to be an attractive target for cancer treatments. However, inhibition of a single metabolic pathway has limited efficacy. In this study, a strategy to concurrently inhibit tumor glycolysis and oxidative phosphorylation is proposed. An antiglycolytic drug and artificially synthesized mitochondria-targeting polypeptide were simultaneously applied to completely deplete the energy source of cancer cells, eventually leading to a synergetic effect of cancer starvation therapy. In vitro results show the mechanism and evidence of the cooperative effect of this combinatorial approach. This study is expected to provide new perspectives of cancer starvation treatments by inhibiting various metabolic pathways.

Keywords:Cell penetrating polypeptide;Metabolism;Glycolysis;Oxidative phosphorylation;Mitochondria;Trimethyl ammonium;2-Deoxy-D-glucose;Cancer starvation therapy

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[2] Martinez-Outschoorn UE, Peiris-Pages M, Pestell RG, Sotgia F, Lisanti MP, Nat. Rev. Clin. Oncol., 14, 11 (2017)

[3] De Berardinis RJ, Chandel NS, Sci. Adv., 2 (2016)

[4] Granchi C, Minutolo F, ChemMedChem, 7, 1318 (2012)

[5] Lopez-Lazaro M, Anticancer. Agents Med. Chem., 8, 305 (2008)

[6] Pelicano H, Martin DS, Xu RH, Huang P, Oncogene, 25, 4633 (2006)

[7] Marchiq I, Pouyssegur J, J. Mol. Med., 94, 155 (2016)

[8] Neri D, Supuran CT, Nat. Rev. Drug Discov., 10, 767 (2011)

[9] Akhavan O, Ghaderi E, Aghayee S, Fereydooni Y, Talebi A, J. Mater. Chem., 22, 13773 (2012)

[10] Yang B, Ding L, Chen Y, Shi J, Adv. Sci., 7 (2020)

[11] Fantin VR, St-Pierre J, Leder P, Cancer Cell, 9, 425 (2006)

[12] Sottnik JL, Lori JC, Rose BJ, Thamm DH, Clin. Exp. Metastasis, 28, 865 (2011)

[13] Weinberg SE, Chandel NS, Nat. Chem. Biol., 11, 9 (2015)

[14] Fulda S, Galluzzi L, Kroemer G, Nat. Rev. Drug Discov., 9, 447 (2010)

[15] Ubah O, Wallace H, Curr. Pharm. Des., 20, 201 (2014)

[16] Cerrato CP, Peptides Mitochondrial Targeting (2018).

[17] Ha JH, Lee DY, Lee SH, Yun CO, Kim YC, Biomaterials, 197, 51 (2019)

[18] Lee DY, et al., Adv. Sci., 6 (2019)

[19] Lee DY, et al., J. Control. Release, 264, 24 (2017)

[20] Yoo J, Rejinold NS, Lee DY, Jon S, Kim YC, J. Control. Release, 264, 89 (2017)

[21] Lee DY, Noh I, Yoo J, Rejinold NS, Kim YC, Acta Biomater., 57, 187 (2017)

[22] Fonseca SB, Pereira MP, Kelley SO, Adv. Drug Deliv. Rev., 61, 953 (2009)

[23] Hancock REW, Lehrer R, Trends Biotechnol., 16, 82 (1998)

[24] Stewart KM, Horton KL, Kelley SO, Org. Biomol. Chem., 6, 2242 (2008)

[25] Yoo J, et al., J. Control. Release, 246, 142 (2017)

[26] Park H, Tsutsumi H, Mihara H, Biomaterials, 34, 4872 (2013)

[27] Kim YC, Ludovice PJ, Prausnitz MR, J. Control. Release, 122, 375 (2007)

[28] Brogden KA, Nat. Rev. Microbiol., 3, 238 (2005)

[29] Jeong YJ, Lee DY, Choe K, Ahn H, Kim P, Park JH, Kim YC, J. Ind. Eng. Chem., 48, 79 (2017)

[30] Ye J, Pei X, Cui H, Yu Z, Lee HJ, Wang JX, Wang X, Sun L, He H, Yang VC, J. Ind. Eng. Chem., 63, 103 (2018)

[31] Lin Y, Zhao M, Bai L, Li H, Xu Y, Li X, Xie J, Zhang Y, Zheng D, J. Ind. Eng. Chem., 97, 256 (2021)

[32] Lu H, et al., Nat. Commun., 2, 206 (2011)

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[34] Butterfield SM, Patel PR, Waters ML, J. Am. Chem. Soc., 124(33), 9751 (2002)

[35] Fokt I, Ziemniak M, Ja A, From Diagnostic to Therapeutic Agents (2020).

[36] Woodward GE, Hudson MT, Cancer Res., 14, 599 (1954)

[37] Xintaropoulou C, et al., Oncotarget, 6, 25677 (2015)

[38] Greenfield NJ, Nat. Protoc., 1, 2876 (2007)

[39] Sivandzade F, Bhalerao A, Cucullo L, Bio-Protocol, 9 (2019)

[40] Fleury C, Mignotte B, Vayssiere JL, Biochimie, 84, 131 (2002)

[41] Morales A, Colell A, Ferna C, Antioxid. Redox Signal., 11, 2685 (2009)

[42] Yang Y, et al., Oncotarget, 5, 11886 (2014)

[43] Manerba M, et al., ChemMedChem, 7, 311 (2012)

[44] Lu QY, Zhang L, Yee JK, Go VLW, Lee WN, Metabolomics, 11, 71 (2014)

[45] Granchi C, Paterni I, Rani R, Minutolo F, Future Med. Chem., 5, 1967 (2013)

[46] Wei R, et al., Food Funct., 9, 5682 (2018)

[47] Hirschhaeuser F, Sattler UGA, Mueller-Klieser W, Cancer Res., 71, 6921 (2011)

[48] Simon HU, Haj-Yehia A, Levi-Schaffer F, Apoptosis, 5, 415 (2000)

[49] Yaromina A, et al., Strahlentherapie Onkol., 188, 431 (2012)

[50] Clement M, et al., Reactive oxygen species, intracellular pH, and cell fate, Proton Homeostasis in Tumorigenesis and Cell Death 49, 2011.

[51] Heiden MGV, Cantley LC, Thompson CB, Science, 324, 1029 (2009)