Hostname: page-component-8448b6f56d-qsmjn Total loading time: 0 Render date: 2024-04-18T21:36:53.779Z Has data issue: false hasContentIssue false
  • English
  • Français

Antitumor activity and antitumor mechanism of triphenylphosphonium chitosan against liver carcinoma

Published online by Cambridge University Press:  14 August 2018

Haochao Huang Open the ORCID record for Haochao Huang [Opens in a new window] ,
Haiwei Wu ,
Yongrui Huang ,
Shuangying Zhang ,
Yuetwai Lam  and
Ningjian Ao
Haochao Huang
Affiliation:
Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China
Haiwei Wu
Affiliation:
College of Chemistry and Materials Science, Jinan University, Guangzhou 510632, China
Yongrui Huang
Affiliation:
Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China
Shuangying Zhang
Affiliation:
Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China
Yuetwai Lam
Affiliation:
Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China
Ningjian Ao*
Affiliation:
Department of Biomedical Engineering, Jinan University, Guangzhou 510632, China
*
a)Address all correspondence to this author. e-mail: aoningjian123@163.com
Get access

Abstract

N-(3-Carboxypropyl) triphenylphosphonium bromide chitosan (TPPB-CS) was synthesized and characterized by FTIR, 1H NMR spectrometer, and Zeta potential. TPPB-CS showed a selectivity-toxicity among cancer cell lines (MG-63 and HepG2 cells) and mouse embryonic fibroblast cells (NIH3T3 cells). A significant effect on inhibiting cell migration in HepG2 cells was observed in vitro, and TPPB-CS could effectively inhibit tumor growth in H22-bearing mice in vivo. Furthermore, the distribution of cell cycle, the level of reactive oxygen species (ROS), mitochondrial transmembrane potential (∆ψm), the expression of tumor necrosis factor α (TNF-α), and vascular endothelial growth factor (VEGF) were examined to investigate the antitumor mechanism of TPPB-CS. The results suggested that the antitumor activity of TPPB-CS may be attributed to delay the cell cycle in S phase, alter the ROS and ∆ψm level, as well as regulate the TNF-α and VEGF secretion. TPPB-CS can become a promising anticancer drug for clinical therapy.

Keywords

triphenylphosphonium chitosanantitumor activity and mechanismliver carcinoma
Type
Article
Information
Journal of Materials Research , Volume 33 , Issue 17 , 14 September 2018 , pp. 2586 - 2597
Copyright
Copyright © Materials Research Society 2018 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Siegel, R.L., Miller, K.D., and Jemal, A.: Cancer statistics, 2016. Ca-Cancer J. Clin. 66, 7 (2016).CrossRefGoogle ScholarPubMed
Pez, F., Lopez, A., Kim, M., Wands, J.R., de Fromentel, C.C., and Merle, P.: Wnt signaling and hepatocarcinogenesis: Molecular targets for the development of innovative anticancer drugs. J. Hepatol. 59, 1107 (2013).CrossRefGoogle ScholarPubMed
Feng, S-S. and Chien, S.: Chemotherapeutic engineering: Application and further development of chemical engineering principles for chemotherapy of cancer and other diseases. Chem. Eng. Sci. 58, 4087 (2003).CrossRefGoogle Scholar
Power, D.G. and Kemeny, N.E.: Chemotherapy for the conversion of unresectable colorectal cancer liver metastases to resection. Crit. Rev. Oncol. Hematol. 79, 251 (2011).CrossRefGoogle Scholar
Rideout, D.C., Calogeropoulou, T., Jaworski, J.S., Dagnino, R. Jr., and McCarthy, M.R.: Phosphonium salts exhibiting selective anti-carcinoma activity in vitro. Anti-Cancer Drug Des. 4, 265 (1989).Google ScholarPubMed
Manetta, A., Gambo, G., Nasseri, A., Podnos, Y.D., Emma, D., Dorion, G., Rawlings, L., Carpenter, P.M., Bustamante, A., Patel, J., and Rideout, D.: Novel phosphonium salts display in vitro and in vivo cytotoxic activity against human ovarian cancer cell lines. Gynecol. Oncol. 60, 203 (1996).CrossRefGoogle ScholarPubMed
Kumar, V. and Malhotra, S.V.: Study on the potential anti-cancer activity of phosphonium and ammonium-based ionic liquids. Bioorg. Med. Chem. Lett. 19, 4643 (2009).CrossRefGoogle ScholarPubMed
Bachowska, B., Kazmierczak-Baranska, J., Cieslak, M., Nawrot, B., Szczęsna, D., Skalik, J., and Bałczewski, P.: High cytotoxic activity of phosphonium salts and their complementary selectivity towards HeLa and K562 cancer cells: Identification of tri-n-butyl-n-hexadecylphosphonium bromide as a highly potent anti-HeLa phosphonium salt. ChemistryOpen 1, 33 (2012).CrossRefGoogle ScholarPubMed
Wang, X-Y., Shao, N-M., Zhang, Q., and Cheng, Y-Y.: Mitochondrial targeting dendrimer allows efficient and safe gene delivery. J. Mater. Chem. B 2, 2546 (2014).CrossRefGoogle Scholar
Boddapati, S.V., Tongcharoensirikul, P., Hanson, R.N., D’Souza, G.G.M., Torchilin, V.P., and Weissig, V.: Mitochondriotropic liposomes. J. Liposome Res. 15, 49 (2015).CrossRefGoogle Scholar
Biswas, S., Dodwadkar, N.S., Piroyan, A., and Torchilin, V.P.: Surface conjugation of triphenylphosphonium to target poly(amidoamine) dendrimers to mitochondria. Biomaterials 33, 4773 (2012).CrossRefGoogle Scholar
Yamada, Y. and Harashima, H.: Mitochondrial drug delivery systems for macromolecule and their therapeutic application to mitochondrial diseases. Adv. Drug Deliv. Rev. 60, 1439 (2008).CrossRefGoogle ScholarPubMed
Zhang, Y., Shen, Y-J., Teng, X-Y., Yan, M-Q., Bi, H., and Morais, P.C.: Mitochondria-targeting nanoplatform with fluorescent carbon dots for long time imaging and magnetic field-enhanced cellular uptake. ACS Appl. Mater. Interfaces 7, 10201 (2015).CrossRefGoogle ScholarPubMed
Wang, X-H., Peng, H-S., Yang, L., You, F-T., Teng, F., Tang, A-W., Zhang, F-J., and Li, X-H.: Poly-L-lysine assisted synthesis of core-shell nanoparticles and conjugation with triphenylphosphonium to target mitochondria. J. Mater. Chem. B 1, 5143 (2013).CrossRefGoogle Scholar
Zhou, J., Zhao, W-Y., Ma, X., Ju, R-J., Li, X-Y., Li, N., Sun, M-G., Shi, J-F., Zhang, C-X., and Lu, W-L.: The anticancer efficacy of paclitaxel liposomes modified with mitochondrial targeting conjugate in resistant lung cancer. Biomaterials 34, 3626 (2013).CrossRefGoogle ScholarPubMed
Callahan, J. and Kopeček, J.: Semitelechelic HPMA copolymers functionalized with triphenylphosphonium as drug carriers for membrane transduction and mitochondrial localization. Biomacromolecules 7, 2347 (2006).CrossRefGoogle ScholarPubMed
Dong, L-F., Jameson, V.J.A., Tilly, D., Prochazka, L., Rohlena, J., Valis, K., Truksa, J., Zobalova, R., Mahdavian, E., Kluckova, K., Stantic, M., Stursa, J., Freeman, R., Witting, P.K., Norberg, E., Goodwin, J., Salvatore, B.A., Novotna, J., Turanek, J., Ledvina, M., Hozak, P., Zhivotovsky, B., Coster, M.J., Ralph, S.J., Smith, R.A., and Neuzil, J.: Mitochondrial targeting of α-tocopheryl succinate enhances its pro-apoptotic efficacy: A new paradigm for effective cancer therapy. Free Radical Biol. Med. 50, 1546 (2011).CrossRefGoogle ScholarPubMed
Cooper, W.A., Bartier, W.A., Rideout, D.C., and Delikatny, E.J.: 1H NMR visible lipids are induced by phosphonium salts and 5-fluorouracil in human breast cancer cells. Magn. Reson. Med. 45, 1001 (2001).CrossRefGoogle ScholarPubMed
Bielski, E.R., Zhong, Q., Brown, M., and da Rocha, S.R.: Effect of the conjugation density of triphenylphosphonium cation on the mitochondrial targeting of poly(amidoamine) dendrimers. Mol. Pharm. 12, 3043 (2015).CrossRefGoogle ScholarPubMed
Wang, B-B., Wang, Y-F., Wu, H., Song, X-J., Guo, X., Zhang, D-M., Ma, X-J., and Tan, M-Q.: A mitochondria-targeted fluorescent probe based on TPP-conjugated carbon dots for both one- and two-photon fluorescence cell imaging. RSC Adv. 4, 49960 (2014).CrossRefGoogle Scholar
Rinaudo, M.: Chitin and chitosan-properties and applications. Prog. Polym. Sci. 31, 603 (2006).CrossRefGoogle Scholar
Liu, Z-H., Jiao, Y-P., Wang, Y-F., Zhou, C-R., and Zhang, Z-Y.: Polysaccharides-based nanoparticles as drug delivery systems. Adv. Drug Deliv. Rev. 60, 1650 (2008).CrossRefGoogle ScholarPubMed
Kean, T. and Thanou, M.: Biodegradation, biodistribution and toxicity of chitosan. Adv. Drug Deliv. Rev. 62, 3 (2010).CrossRefGoogle ScholarPubMed
Hsu, S.H., Chang, Y-B., Tsai, C.L., Fu, K-Y., Wang, S-H., and Tseng, H.J.: Characterization and biocompatibility of chitosan nanocomposites. Colloids Surf., B 85, 198 (2011).CrossRefGoogle ScholarPubMed
Maeda, Y. and Kimura, Y.: Antitumor effects of various low-molecular-weight chitosans are due to increased natural killer activity of intestinal intraepithelial lymphocytes in sarcoma 180-bearing mice. J. Nutr. 134, 945 (2004).CrossRefGoogle ScholarPubMed
Ta, H.T., Dass, C.R., and Dunstan, D.E.: Injectable chitosan hydrogels for localised cancer therapy. J. Controlled Release 126, 205 (2008).CrossRefGoogle ScholarPubMed
Gibot, L., Chabaud, S., Bouhout, S., Bolduc, S., Auger, F.A., and Moulin, V.J.: Anticancer properties of chitosan on human melanoma are cell line dependent. Int. J. Biol. Macromol. 72, 370 (2015).CrossRefGoogle ScholarPubMed
Wang, L., Xu, X-F., Guo, S-R., Peng, Z-X., and Tang, T-T.: Novel water soluble phosphonium chitosan derivatives: Synthesis, characterization and cytotoxicity studies. Int. J. Biol. Macromol. 48, 375 (2011).CrossRefGoogle ScholarPubMed
Qian, C-Y., Xu, X-F., Shen, Y-Y., Li, Y-G., and Guo, S-R.: Synthesis and preliminary cellular evaluation of phosphonium chitosan derivatives as novel non-viral vector. Carbohydr. Polym. 97, 676 (2013).CrossRefGoogle ScholarPubMed
Rajamani, T., Muthu, S., and Karabacak, M.: Electronic absorption, vibrational spectra, nonlinear optical properties, NBO analysis and thermodynamic properties of N-(4-nitro-2-phenoxyphenyl) methanesulfonamide molecule by ab initio HF and density functional methods. Spectrochim. Acta, Part A 108, 186 (2013).CrossRefGoogle ScholarPubMed
Li, C., Liu, Y., Zeng, Q-Y., and Ao, N-J.: Preparation and antimicrobial activity of quaternary phosphonium modified epoxidized natural rubber. Mater. Lett. 93, 145 (2013).CrossRefGoogle Scholar
Chen, S-G., Wang, J-F., Xue, C-H., Li, H., Sun, B-B., Xue, Y., and Chai, W-G.: Sulfation of a squid ink polysaccharide and its inhibitory effect on tumor cell metastasis. Carbohydr. Polym. 81, 560 (2010).CrossRefGoogle Scholar
Jiang, Z-W., Han, B-Q., Li, H., Yang, Y., and Liu, W-S.: Carboxymethyl chitosan represses tumor angiogenesis in vitro andin vivo. Carbohydr. Polym. 129, 1 (2015).CrossRefGoogle Scholar
Jiang, Z-W., Han, B-Q., Li, H., Li, X-H., Yang, Y., and Liu, W-S.: Preparation and anti-tumor metastasis of carboxymethyl chitosan. Carbohydr. Polym. 125, 53 (2015).CrossRefGoogle ScholarPubMed
Katona, C., Kralovánszky, J., Rosta, A., Pandi, E., Fónyad, G., Tóth, K., and Jeney, A.: Putative role of dihydropyrimidine dehydrogenase in the toxic side effect of 5-fluorouracil in colorectal cancer patients. Oncology 55, 468 (1998).CrossRefGoogle ScholarPubMed
Wettergren, Y., Carlsson, G., Odin, E., and Gustavsson, B.: Pretherapeutic uracil and dihydrouracil levels of colorectal cancer patients are associated with sex and toxic side effects during adjuvant 5-fluorouracil–based chemotherapy. Cancer 118, 2935 (2012).CrossRefGoogle ScholarPubMed
Pelicano, H., Carney, D., and Huang, P.: ROS stress in cancer cells and therapeutic implications. Drug Resist. Updates 7, 97 (2004).CrossRefGoogle ScholarPubMed
Wu, J-M., Dipietrantonio, A.M., and Hsieh, T.C.: Mechanism of fenretinide (4-HPR)-induced cell death. Apoptosis 6, 377 (2001).CrossRefGoogle ScholarPubMed
Li, J-Y., Xu, Z-J., Tan, M-Y., Su, W-K., and Gong, X-G.: 3-(4-(Benzo[d]thiazol-2-yl)-1-phenyl-1H-pyrazol-3-yl) phenyl acetate induced HepG2 cell apoptosis through a ROS-mediated pathway. Chem. Biol. Interact. 183, 341 (2010).CrossRefGoogle ScholarPubMed
Ralph, S.J., Moreno-Sánchez, R., Neuzil, J., and Rodríguez-Enríquez, S.: Inhibitors of succinate: Quinone reductase/complex II regulate production of mitochondrial reactive oxygen species and protect normal cells from ischemic damage but induce specific cancer cell death. Pharm. Res. 28, 2695 (2011).CrossRefGoogle ScholarPubMed
Hileman, E.O., Liu, J-S., Albitar, M., Keating, M.J., and Huang, P.: Intrinsic oxidative stress in cancer cells: A biochemical basis for therapeutic selectivity. Canc. Chemother. Pharmacol. 53, 209 (2004).CrossRefGoogle ScholarPubMed
Qin, Y., Chen, F-D., Zhou, L., Gong, X-G., and Han, Q-F.: Proliferative and anti-proliferative effects of thymosin α1 on cells are associated with manipulation of cellular ROS levels. Chem. Biol. Interact. 180, 383 (2009).CrossRefGoogle ScholarPubMed
Qin, Y., Pan, X., Tang, T-T., Zhou, L., and Gong, X-G.: Anti-proliferative effects of the novel squamosamide derivative (FLZ) on HepG2 human hepatoma cells by regulating the cell cycle-related proteins are associated with decreased Ca2+/ROS levels. Chem. Biol. Interact. 193, 246 (2011).CrossRefGoogle Scholar
Ohm, J.E. and Carbone, D.P.: VEGF as a mediator of tumor-associated immunodeficiency. Immunol. Res. 23, 263 (2001).CrossRefGoogle ScholarPubMed
Ni, C-S., Sun, B-C., Dong, X-Y., Sun, T., Zhao, N., Liu, Y-R., and Gu, Q.: Promoting melanoma growth and metastasis by enhancing VEGF expression. Contemp. Oncol. 16, 526 (2012).Google ScholarPubMed
Varfolomeev, E.E. and Ashkenazi, A.: Tumor necrosis factor: An apoptosis JuNKie? Cell 116, 491 (2004).CrossRefGoogle ScholarPubMed
Ji, H., Cao, R-H., Yang, Y-L., Zhang, Y., Iwamoto, H., Lim, S., Nakamura, M., Andersson, P., Wang, J., Sun, Y-P., Dissing, S., He, X., Yang, X-J., and Cao, Y-H.: TNFR1 mediates TNF-a-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling. Nat. Commun. 5, 4944 (2014).CrossRefGoogle Scholar
Li, B., Vincent, A., Cates, J., Brantley-Sieders, D.M., Polk, D.B., and Young, P.P.: Low levels of tumor necrosis factor α increase tumor growth by inducing an endothelial phenotype of monocytes recruited to the tumor site. Cancer Res. 69, 338 (2009).CrossRefGoogle ScholarPubMed
Kim, S., Takahashi, H., Lin, W-W., Descargues, P., Grivennikov, S.I., Kim, Y., Luo, J-L., and Karin, M.: Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457, 102 (2009).CrossRefGoogle ScholarPubMed
Mantovani, A., Allavena, P., Sica, A., and Balkwill, F.: Cancer-related inflammation. Nature 454, 436 (2008).CrossRefGoogle ScholarPubMed