Strategy to Enhance the Therapeutic Effect of Doxorubicin in Human Hepatocellular Carcinoma by Selenocystine, a Synergistic Agent That Regulates the ROS-mediated Signaling

Overview

Journal Oncotarget

Specialty Oncology

Date 2014 May 7

PMID 24797310

Citations 33

Authors

Cundong Fan

Wenjie Zheng

Xiaoyan Fu

Xiaoling Li

Yum-Shing Wong

Tianfeng Chen

Affiliations

Soon will be listed here.

Abstract

Doxorubicin-based chemotherapy represents one of the most effective ways in combating human cancers. However, its clinical use is limited by severe side effects. Selenocystine (SeC) is a natural available selenoamino acid with novel anticancer efficacy. In this study, we used SeC to sensitize HepG2 human hepatocellular carcinoma (HCC) cells to DOX, and to achieve anticancer synergism in vitro and in vivo. Treatment with DOX dose-dependently reduced HepG2 cell viability through initiating cell apoptosis and strong G2/M phase cell cycle arrest. Mechanistic studies indicated that this sensitization of SeC to DOX was achieved by triggering inactivation of ERK and AKT and DNA damage through reactive oxygen species (ROS) overproduction. Pretreatment with inhibitors of ERK and AKT markedly enhanced combined treatment-induced cell killing, indicating that combined treatment-induced HCC cell killing with ERK- and AKT-dependent manner. Furthermore, inhibition of ROS effectively attenuated combined treatment-induced DNA damage and inactivation of ERK and AKT. Additionally, xenograft hepatocellular carcinoma growth was also effectively inhibited by combined treatment through induction of cell apoptosis in vivo. Taken together, our results suggest that the strategy to use SeC and DOX in combination could be a highly efficient way to achieve anticancer synergism against HCC.

Citing Articles

Exploring Selenium-Functionalized Hydroxyapatite Using Organic Selenocystine for Antitumor Applications.

Barbanente A, Di Cosola A, Degli Esposti L, Iafisco M, Niso M, Margiotta N Materials (Basel). 2025; 18(5).

PMID: 40077269 PMC: 11901003. DOI: 10.3390/ma18051043.

Selenium in cancer management: exploring the therapeutic potential.

He L, Zhang L, Peng Y, He Z Front Oncol. 2025; 14():1490740.

PMID: 39839762 PMC: 11746096. DOI: 10.3389/fonc.2024.1490740.

and antitumor activity of tomatine in hepatocellular carcinoma.

Echeverria C, Martin A, Simon F, Salas C, Nazal M, Varela D Front Pharmacol. 2022; 13:1003264.

PMID: 36160442 PMC: 9501894. DOI: 10.3389/fphar.2022.1003264.

Selenocystine-Derived Label-Free Fluorescent Schiff Base Nanocomplex for siRNA Delivery Synergistically Kills Cancer Cells.

Liu Y, Yang H, Liu Q, Pan M, Wang D, Pan S Molecules. 2022; 27(4).

PMID: 35209090 PMC: 8878402. DOI: 10.3390/molecules27041302.

Functionalized Selenium Nanotherapeutics Synergizes With Zoledronic Acid to Suppress Prostate Cancer Cell Growth Through Induction of Mitochondria-Mediated Apoptosis and Cell Cycle S Phase Arrest.

An Y, Zhao J Front Oncol. 2021; 11:685784.

PMID: 34168998 PMC: 8219073. DOI: 10.3389/fonc.2021.685784.

References

Weiss R . The anthracyclines: will we ever find a better doxorubicin?. Semin Oncol. 1992; 19(6):670-86. View

Hu H, Jiang C, Ip C, Rustum Y, Lu J . Methylseleninic acid potentiates apoptosis induced by chemotherapeutic drugs in androgen-independent prostate cancer cells. Clin Cancer Res. 2005; 11(6):2379-88. DOI: 10.1158/1078-0432.CCR-04-2084. View

Takemura G, Fujiwara H . Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog Cardiovasc Dis. 2007; 49(5):330-52. DOI: 10.1016/j.pcad.2006.10.002. View

Sinha R, El-Bayoumy K . Apoptosis is a critical cellular event in cancer chemoprevention and chemotherapy by selenium compounds. Curr Cancer Drug Targets. 2004; 4(1):13-28. DOI: 10.2174/1568009043481614. View

Chen T, Zheng W, Wong Y, Yang F . Mitochondria-mediated apoptosis in human breast carcinoma MCF-7 cells induced by a novel selenadiazole derivative. Biomed Pharmacother. 2008; 62(2):77-84. DOI: 10.1016/j.biopha.2007.12.002. View

Li D, Graef G, Yee J, Yan L . Dietary supplementation with high-selenium soy protein reduces pulmonary metastasis of melanoma cells in mice. J Nutr. 2004; 134(6):1536-40. DOI: 10.1093/jn/134.6.1536. View

Llovet J . Updated treatment approach to hepatocellular carcinoma. J Gastroenterol. 2005; 40(3):225-35. DOI: 10.1007/s00535-005-1566-3. View

Singh R, Dhanalakshmi S, Agarwal R . Phytochemicals as cell cycle modulators--a less toxic approach in halting human cancers. Cell Cycle. 2002; 1(3):156-61. View

Norbury C, Zhivotovsky B . DNA damage-induced apoptosis. Oncogene. 2004; 23(16):2797-808. DOI: 10.1038/sj.onc.1207532. View

10.

Llovet J, Burroughs A, Bruix J . Hepatocellular carcinoma. Lancet. 2003; 362(9399):1907-17. DOI: 10.1016/S0140-6736(03)14964-1. View

11.

Yamaguchi M, Fujimori-Tonou N, Yoshimura Y, Kishi T, Okamoto H, Masai I . Mutation of DNA primase causes extensive apoptosis of retinal neurons through the activation of DNA damage checkpoint and tumor suppressor p53. Development. 2008; 135(7):1247-57. DOI: 10.1242/dev.011015. View

12.

Liu C, Liu Z, Li M, Li X, Wong Y, Ngai S . Enhancement of auranofin-induced apoptosis in MCF-7 human breast cells by selenocystine, a synergistic inhibitor of thioredoxin reductase. PLoS One. 2013; 8(1):e53945. PMC: 3544722. DOI: 10.1371/journal.pone.0053945. View

13.

Li S, Zhou Y, Wang R, Zhang H, Dong Y, Ip C . Selenium sensitizes MCF-7 breast cancer cells to doxorubicin-induced apoptosis through modulation of phospho-Akt and its downstream substrates. Mol Cancer Ther. 2007; 6(3):1031-8. DOI: 10.1158/1535-7163.MCT-06-0643. View

14.

Roos W, Kaina B . DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 2012; 332(2):237-48. DOI: 10.1016/j.canlet.2012.01.007. View

15.

Gewirtz D . A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999; 57(7):727-41. DOI: 10.1016/s0006-2952(98)00307-4. View

16.

Gedaly R, Angulo P, Hundley J, Daily M, Chen C, Koch A . PI-103 and sorafenib inhibit hepatocellular carcinoma cell proliferation by blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. Anticancer Res. 2010; 30(12):4951-8. PMC: 3141822. View

17.

Noto A, De Vitis C, Roscilli G, Fattore L, Malpicci D, Marra E . Combination therapy with anti-ErbB3 monoclonal antibodies and EGFR TKIs potently inhibits non-small cell lung cancer. Oncotarget. 2013; 4(8):1253-65. PMC: 3787155. DOI: 10.18632/oncotarget.1141. View

18.

Pellegata N, Antoniono R, Redpath J, Stanbridge E . DNA damage and p53-mediated cell cycle arrest: a reevaluation. Proc Natl Acad Sci U S A. 1996; 93(26):15209-14. PMC: 26382. DOI: 10.1073/pnas.93.26.15209. View

19.

Fan C, Chen J, Wang Y, Wong Y, Zhang Y, Zheng W . Selenocystine potentiates cancer cell apoptosis induced by 5-fluorouracil by triggering reactive oxygen species-mediated DNA damage and inactivation of the ERK pathway. Free Radic Biol Med. 2013; 65:305-316. DOI: 10.1016/j.freeradbiomed.2013.07.002. View

20.

Schomburg L, Schweizer U, Kohrle J . Selenium and selenoproteins in mammals: extraordinary, essential, enigmatic. Cell Mol Life Sci. 2004; 61(16):1988-95. PMC: 11138627. DOI: 10.1007/s00018-004-4114-z. View