Zinc-Doped Copper Oxide Nanocomposites Inhibit the Growth of Pancreatic Cancer by Inducing Autophagy Through AMPK/mTOR Pathway

Overview

Journal Front Pharmacol

Date 2019 Apr 20

PMID 31001120

Citations 10

Authors

Xiao Li

Huanli Xu

Cong Li

Gan Qiao

Ammad Ahmad Farooqi

Aharon Gedanken

Xiaohui Liu

Xiukun Lin

Affiliations

Soon will be listed here.

Abstract

Zinc doped copper oxide nanocomposites (Zn-CuO NPs) is a novel doped metal nanomaterial synthesized by our group using the sonochemical method. Our previous studies have shown that Zn-CuO NPs could inhibit cancer cell proliferation by inducing apoptosis via ROS-mediated pathway. In the present study, we studied the anticancer effect of Zn-CuO NPs on human pancreatic cancer cells. MTS assay revealed that Zn-CuO NPs was able to inhibit cancer cell growth. TEM, flow cytometry and fluorescence microscope analysis showed that Zn-CuO NPs induced autophagy significantly; the number of autophagosomes increased obviously in cells treated with Zn-CuO NPs. Western blot analysis revealed that treatment with the NPs resulted in activation of AMPK/mTOR pathway in both AsPC-1 and MIA Paca-2 cells in dose dependent manners. Moreover, in the presence of AMPK activator AMPKinone, the protein level of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I increased, while the protein expression of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I decreased in the presence of AMPK inhibitor Compound C. study using xenograft mice revealed that Zn-CuO NPs significantly inhibited tumor growth with low toxicity. Our study confirms that Zn-CuO NPs inhibit the tumor growth both and for pancreatic cancer. AMPK/mTOR pathway plays an important role in the NPs induced inhibition of tumor growth.

Citing Articles

Mechanisms of Copper-Induced Autophagy and Links with Human Diseases.

Fu Y, Zeng S, Wang Z, Huang H, Zhao X, Li M Pharmaceuticals (Basel). 2025; 18(1).

PMID: 39861161 PMC: 11768742. DOI: 10.3390/ph18010099.

Trace elements in pancreatic cancer.

Yanjun Y, Jing Z, Yifei S, Gangzhao G, Chenxin Y, Qiang W Cancer Med. 2024; 13(14):e7454.

PMID: 39015024 PMC: 11252496. DOI: 10.1002/cam4.7454.

Huang Y, Gong P, Su L, Zhang M Sci Rep. 2023; 13(1):20870.

PMID: 38012210 PMC: 10682027. DOI: 10.1038/s41598-023-47223-4.

Micelle encapsulation zinc-doped copper oxide nanocomposites reverse Olaparib resistance in ovarian cancer by disrupting homologous recombination repair.

Yi J, Luo X, Xing J, Gedanken A, Lin X, Zhang C Bioeng Transl Med. 2023; 8(3):e10507.

PMID: 37206208 PMC: 10189445. DOI: 10.1002/btm2.10507.

Cu-doped TiO nanoparticles improve local antitumor immune activation and optimize dendritic cell vaccine strategies.

Hesemans E, Saffarzadeh N, Maksoudian C, Izci M, Chu T, Luci C J Nanobiotechnology. 2023; 21(1):87.

PMID: 36915084 PMC: 10009859. DOI: 10.1186/s12951-023-01844-z.

References

Kondo Y, Kanzawa T, Sawaya R, Kondo S . The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005; 5(9):726-34. DOI: 10.1038/nrc1692. View

White E, DiPaola R . The double-edged sword of autophagy modulation in cancer. Clin Cancer Res. 2009; 15(17):5308-16. PMC: 2737083. DOI: 10.1158/1078-0432.CCR-07-5023. View

Rasmussen J, Martinez E, Louka P, Wingett D . Zinc oxide nanoparticles for selective destruction of tumor cells and potential for drug delivery applications. Expert Opin Drug Deliv. 2010; 7(9):1063-77. PMC: 2924765. DOI: 10.1517/17425247.2010.502560. View

Baek Y, An Y . Microbial toxicity of metal oxide nanoparticles (CuO, NiO, ZnO, and Sb2O3) to Escherichia coli, Bacillus subtilis, and Streptococcus aureus. Sci Total Environ. 2011; 409(8):1603-8. DOI: 10.1016/j.scitotenv.2011.01.014. View

Rosenfeldt M, Ryan K . The multiple roles of autophagy in cancer. Carcinogenesis. 2011; 32(7):955-63. PMC: 3128556. DOI: 10.1093/carcin/bgr031. View

Wu Y, Yang L, Shi X, Li I, Biazik J, Ratinac K . The selective growth inhibition of oral cancer by iron core-gold shell nanoparticles through mitochondria-mediated autophagy. Biomaterials. 2011; 32(20):4565-73. DOI: 10.1016/j.biomaterials.2011.03.006. View

Alers S, Loffler A, Wesselborg S, Stork B . Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol. 2011; 32(1):2-11. PMC: 3255710. DOI: 10.1128/MCB.06159-11. View

Khan M, Mohammad A, Patil G, Naqvi S, Chauhan L, Ahmad I . Induction of ROS, mitochondrial damage and autophagy in lung epithelial cancer cells by iron oxide nanoparticles. Biomaterials. 2011; 33(5):1477-88. DOI: 10.1016/j.biomaterials.2011.10.080. View

Sun T, Yan Y, Zhao Y, Guo F, Jiang C . Copper oxide nanoparticles induce autophagic cell death in A549 cells. PLoS One. 2012; 7(8):e43442. PMC: 3423358. DOI: 10.1371/journal.pone.0043442. View

10.

Li L, Chen Y, Gibson S . Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activation. Cell Signal. 2012; 25(1):50-65. DOI: 10.1016/j.cellsig.2012.09.020. View

11.

Kim J, Kim Y, Fang C, Russell R, Kim J, Fan W . Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell. 2013; 152(1-2):290-303. PMC: 3587159. DOI: 10.1016/j.cell.2012.12.016. View

12.

Zhao X, Wang S, Wu Y, You H, Lv L . Acute ZnO nanoparticles exposure induces developmental toxicity, oxidative stress and DNA damage in embryo-larval zebrafish. Aquat Toxicol. 2013; 136-137:49-59. DOI: 10.1016/j.aquatox.2013.03.019. View

13.

Malka E, Perelshtein I, Lipovsky A, Shalom Y, Naparstek L, Perkas N . Eradication of multi-drug resistant bacteria by a novel Zn-doped CuO nanocomposite. Small. 2013; 9(23):4069-76. DOI: 10.1002/smll.201301081. View

14.

Roy R, Singh S, Chauhan L, Das M, Tripathi A, Dwivedi P . Zinc oxide nanoparticles induce apoptosis by enhancement of autophagy via PI3K/Akt/mTOR inhibition. Toxicol Lett. 2014; 227(1):29-40. DOI: 10.1016/j.toxlet.2014.02.024. View

15.

Dizaj S, Lotfipour F, Barzegar-Jalali M, Zarrintan M, Adibkia K . Antimicrobial activity of the metals and metal oxide nanoparticles. Mater Sci Eng C Mater Biol Appl. 2014; 44:278-84. DOI: 10.1016/j.msec.2014.08.031. View

16.

Lin J, Huang Z, Wu H, Zhou W, Jin P, Wei P . Inhibition of autophagy enhances the anticancer activity of silver nanoparticles. Autophagy. 2014; 10(11):2006-20. PMC: 4502813. DOI: 10.4161/auto.36293. View

17.

Rigacci S, Miceli C, Nediani C, Berti A, Cascella R, Pantano D . Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: a mechanistic insight. Oncotarget. 2015; 6(34):35344-57. PMC: 4742109. DOI: 10.18632/oncotarget.6119. View

18.

Papinski D, Kraft C . Regulation of Autophagy By Signaling Through the Atg1/ULK1 Complex. J Mol Biol. 2016; 428(9 Pt A):1725-41. DOI: 10.1016/j.jmb.2016.03.030. View

19.

Shimoji M, Shimizu S, Sato K, Suda K, Kobayashi Y, Tomizawa K . Clinical and pathologic features of lung cancer expressing programmed cell death ligand 1 (PD-L1). Lung Cancer. 2016; 98:69-75. DOI: 10.1016/j.lungcan.2016.04.021. View

20.

Zhang X, Yin H, Li Z, Zhang T, Yang Z . Nano-TiO induces autophagy to protect against cell death through antioxidative mechanism in podocytes. Cell Biol Toxicol. 2016; 32(6):513-527. DOI: 10.1007/s10565-016-9352-y. View