Carvedilol Suppresses Malignant Proliferation of Mammary Epithelial Cells Through Inhibition of the ROS‑mediated PI3K/AKT Signaling Pathway

Overview

Journal Oncol Rep

Specialty Oncology

Date 2018 Nov 29

PMID 30483797

Citations 15

Authors

Zhongbing Ma

Xingli Liu

Qiang Zhang

Zhigang Yu

Dezong Gao

Affiliations

Soon will be listed here.

Abstract

Reactive oxygen species (ROS) cause oncogenic mutations through direct interaction with DNA. Carvedilol (CAR) exhibits antioxidative activity, and pre‑clinical studies have identified that CAR may prevent malignant transformation in certain carcinogenic models. This suggests that CAR may be a potential agent in cancer prevention. In the present study, non‑cancerous MCF‑10A cells were used as a model to investigate the chemopreventive effect of CAR on benzo(a)pyrene (BaP)‑induced cellular carcinogenesis. It was identified that CAR had the ability to eliminate BaP‑induced ROS production and subsequent DNA damage. CAR/BaP activated the ROS‑mediated phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT)Thr308 signaling pathway, whereas the effectors of the PI3K/AKT signaling pathway, murine double minute 2 (MDM2) and p53Ser15, served important functions in the BaP/CAR‑mediated MCF10A cellular transformation. The results of the present study indicated that CAR may be a novel chemopreventive agent, notably in the prevention of estrogen receptor‑negative breast cancer. The antioxidant effects of CAR may contribute to its chemopreventive activity.

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References

Mayo L, Donner D . A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A. 2001; 98(20):11598-603. PMC: 58775. DOI: 10.1073/pnas.181181198. View

Zhou B, Liao Y, Xia W, Zou Y, Spohn B, Hung M . HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol. 2001; 3(11):973-82. DOI: 10.1038/ncb1101-973. View

Cooke M, Evans M, Dizdaroglu M, Lunec J . Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 2003; 17(10):1195-214. DOI: 10.1096/fj.02-0752rev. View

Yue T, Cheng H, Lysko P, McKenna P, Feuerstein R, Gu J . Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther. 1992; 263(1):92-8. View

Oliveira P, Goncalves L, Monteiro P, Providencia L, Moreno A . Are the antioxidant properties of carvedilol important for the protection of cardiac mitochondria?. Curr Vasc Pharmacol. 2005; 3(2):147-58. DOI: 10.2174/1570161053586903. View

Siriwardhana N, Wang H . Precancerous carcinogenesis of human breast epithelial cells by chronic exposure to benzo[a]pyrene. Mol Carcinog. 2007; 47(5):338-48. DOI: 10.1002/mc.20392. View

Paajarvi G, Jernstrom B, Seidel A, Stenius U . Anti-diol epoxide of benzo[a]pyrene induces transient Mdm2 and p53 Ser15 phosphorylation, while anti-diol epoxide of dibenzo[a,l]pyrene induces a nontransient p53 Ser15 phosphorylation. Mol Carcinog. 2007; 47(4):301-9. DOI: 10.1002/mc.20385. View

Song X, Siriwardhana N, Rathore K, Lin D, Wang H . Grape seed proanthocyanidin suppression of breast cell carcinogenesis induced by chronic exposure to combined 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene. Mol Carcinog. 2010; 49(5):450-63. PMC: 3152701. DOI: 10.1002/mc.20616. View

Erguven M, Yazihan N, Aktas E, Sabanci A, Li C, Oktem G . Carvedilol in glioma treatment alone and with imatinib in vitro. Int J Oncol. 2010; 36(4):857-66. DOI: 10.3892/ijo_00000563. View

10.

Sigounas G, Hairr J, Cooke C, Owen J, Asch A, Weidner D . Role of benzo[alpha]pyrene in generation of clustered DNA damage in human breast tissue. Free Radic Biol Med. 2010; 49(1):77-87. DOI: 10.1016/j.freeradbiomed.2010.03.018. View

11.

Vincent E, Elder D, Thomas E, Phillips L, Morgan C, Pawade J . Akt phosphorylation on Thr308 but not on Ser473 correlates with Akt protein kinase activity in human non-small cell lung cancer. Br J Cancer. 2011; 104(11):1755-61. PMC: 3111153. DOI: 10.1038/bjc.2011.132. View

12.

Freedman A, Yu B, Gail M, Costantino J, Graubard B, Vogel V . Benefit/risk assessment for breast cancer chemoprevention with raloxifene or tamoxifen for women age 50 years or older. J Clin Oncol. 2011; 29(17):2327-33. PMC: 3107748. DOI: 10.1200/JCO.2010.33.0258. View

13.

Umannova L, Machala M, Topinka J, Schmuczerova J, Krcmar P, Neca J . Benzo[a]pyrene and tumor necrosis factor-α coordinately increase genotoxic damage and the production of proinflammatory mediators in alveolar epithelial type II cells. Toxicol Lett. 2011; 206(2):121-9. DOI: 10.1016/j.toxlet.2011.06.029. View

14.

Su C, Wang C, Lan K, Li C, Chao Y, Lin H . Akt phosphorylation at Thr308 and Ser473 is required for CHIP-mediated ubiquitination of the kinase. Cell Signal. 2011; 23(11):1824-30. DOI: 10.1016/j.cellsig.2011.06.018. View

15.

Astle M, Hannan K, Ng P, Lee R, George A, Hsu A . AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy. Oncogene. 2011; 31(15):1949-62. PMC: 3325598. DOI: 10.1038/onc.2011.394. View

16.

Gupta S, Hevia D, Patchva S, Park B, Koh W, Aggarwal B . Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy. Antioxid Redox Signal. 2011; 16(11):1295-322. PMC: 3324815. DOI: 10.1089/ars.2011.4414. View

17.

Kastrati I, Edirisinghe P, Hemachandra L, Chandrasena E, Choi J, Wang Y . Raloxifene and desmethylarzoxifene block estrogen-induced malignant transformation of human breast epithelial cells. PLoS One. 2011; 6(11):e27876. PMC: 3226622. DOI: 10.1371/journal.pone.0027876. View

18.

Nkrumah-Elie Y, Reuben J, Hudson A, Taka E, Badisa R, Ardley T . Diallyl trisulfide as an inhibitor of benzo(a)pyrene-induced precancerous carcinogenesis in MCF-10A cells. Food Chem Toxicol. 2012; 50(7):2524-30. PMC: 3374924. DOI: 10.1016/j.fct.2012.04.010. View

19.

Son Y, Pratheeshkumar P, Wang L, Wang X, Fan J, Kim D . Reactive oxygen species mediate Cr(VI)-induced carcinogenesis through PI3K/AKT-dependent activation of GSK-3β/β-catenin signaling. Toxicol Appl Pharmacol. 2013; 271(2):239-48. PMC: 3742697. DOI: 10.1016/j.taap.2013.04.036. View

20.

Mohapatra P, Preet R, Das D, Satapathy S, Siddharth S, Choudhuri T . The contribution of heavy metals in cigarette smoke condensate to malignant transformation of breast epithelial cells and in vivo initiation of neoplasia through induction of a PI3K-AKT-NFκB cascade. Toxicol Appl Pharmacol. 2013; 274(1):168-79. DOI: 10.1016/j.taap.2013.09.028. View