Skip to main content
SpringerLink
Log in

Toosendanin mediates cisplatin sensitization through targeting Annexin A4/ATP7A in non-small cell lung cancer cells

  • Original Paper
  • Published:
Journal of Natural Medicines Aims and scope Submit manuscript

Abstract

Cisplatin (CDDP) is used in the treatment of non-small cell lung cancer (NSCLC), but due to the development of resistance, the benefit has been limited. Toosendanin (TSN) has shown therapeutic effects on NSCLC; however, the role of TSN on CDDP sensitization in NSCLC remains unknown. The antitumor effects of TSN and CDDP sensitization mediated by TSN were explored. TSN was added in various amounts to measure dose- and time-dependent cytotoxicity. Intracellular CDDP was detected by high-performance liquid chromatography. The protein levels of ATP7A, ATP7B, hCTR1, MRP-2, P-gp and Annexin A4 (Anxa4) were analyzed. The tests were conducted using normal NSCLC (A549 cell line) and CDDP-resistant cells (A549/DDP cell line). Anxa4 promotes CDDP resistance by regulating ATP7A, so Anxa4 was overexpressed and silenced and also transfected with pcMV6 or siRNA/ATP7A, respectively. Mechanistic investigations revealed that TSN decreased relative viability in NSCLC cells. Remarkably, TSN significantly enhanced CDDPsensitization in invalid doses. TSN downregulated Anxa4 expression, enhanced intracellular CDDP, and had no effect on MRP-2, P-gp, ATP7A, ATP7B or hCTR1. Subsequently, overexpression of Anxa4 led to a significant decrease in intracellular CDDP concentration. The adjustment of CDDP concentration regulated by TSN disappeared in Anxa4 or ATP7A-silenced cells. TSN also enhanced CDDP sensitization in single ATP7A-overexpressing cells, but had no effect on cells with simultaneous ATP7A overexpression and Anxa4 silencing. The present study suggests that TSN can mediate CDDP sensitization in NSCLC through downregulation of Anxa4.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Hildebrandt MA, Gu J, Wu X (2009) Pharmacogenomics of platinum-based chemotherapy in NSCLC. Expert Opin Drug Metab Toxicol 5(7):745–755

    Article  CAS  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67(1):7–30

    Article  Google Scholar 

  3. Zornosa C, Vandergrift JL, Kalemkerian GP, Ettinger DS, Rabin MS, Reid M, Otterson GA, Koczywas M, D’Amico TA, Niland JC, Mamet R, Pisters KM (2012) First-line systemic therapy practice patterns and concordance with NCCN guidelines for patients diagnosed with metastatic NSCLC treated at NCCN institutions. J Natl Compr Canc Netw 10(7):847–856

    Article  CAS  Google Scholar 

  4. Perez RP (1998) Cellular and molecular determinants of cisplatin resistance. Eur J Cancer 34(10):1535–1542

    Article  CAS  Google Scholar 

  5. Tiseo M, Franciosi V, Grossi F, Ardizzoni A (2006) Adjuvant chemotherapy for non-small cell lung cancer: ready for clinical practice? Eur J Cancer 42(1):8–16

    Article  CAS  Google Scholar 

  6. Martin LP, Hamilton TC, Schilder RJ (2008) Platinum resistance: the role of DNA repair pathways. Clin Cancer Res 14(5):1291–1295

    Article  CAS  Google Scholar 

  7. Stewart DJ (2007) Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol 63(1):12–31

    Article  Google Scholar 

  8. Zisowsky J, Koegel S, Leyers S, Devarakonda K, Kassack MU, Osmak M, Jaehde U (2007) Relevance of drug uptake and efflux for cisplatin sensitivity of tumor cells. Biochem Pharmacol 73(2):298–307

    Article  CAS  Google Scholar 

  9. Ling CQ, Yue XQ, Ling C (2014) Three advantages of using traditional Chinese medicine to prevent and treat tumor. J Integr Med 12(4):331–335

    Article  Google Scholar 

  10. Tang MZ, Wang ZF, Shi YL (2004) A study of ultrasound-assisted extraction of toosendanin with water from bark of melia toosendan sieb. T zucc. J Southwest Univ Natl (Nat Sci Ed, Chin) 30(8):714–717

  11. Tang MZ, Wang ZF, Shi YL (2004) Involvement of cytochrome c release and caspase activation in toosendanin-induced PC12 cell apoptosis. Toxicology 201(1–3):131–138

    Google Scholar 

  12. Yu JC, Min ZD, Ip NY (2004) Melia toosendan regulates PC12 Cell differentiation via the activation of protein kinase A and extracellular signal-regulated kinases. Neurosignals 13(5):248–257

    Article  Google Scholar 

  13. Zhang B, Wang ZF, Tang MZ, Shi YL (2005) Growth inhibition and apoptosis-induced effect on human cancer cells of toosendanin, a triterpenoid derivative from chinese traditional medicine. Invest New Drugs 23(6):547–553

    Article  CAS  Google Scholar 

  14. Wang G, Feng CC, Chu SJ, Zhang R, Lu YM, Zhu JS, Zhang J (2015) Toosendanin inhibits growth and induces apoptosis in colorectal cancer cells through suppression of AKT/GSK-3β/β-catenin pathway. Int J Oncol 47(5):1767–1774

    Article  CAS  Google Scholar 

  15. Harrington CF, Le Pla RC, Jones GD, Thomas AL, Farmer PB (2010) Determination of cisplatin 1,2-intrastrand guanine-guanine DNA adducts in human leukocytes by high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. Chem Res Toxicol 23(8):1313–1321

    Article  CAS  Google Scholar 

  16. Cui Y, König J, Buchholz JK, Spring H, Leier I, Keppler D (1999) Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol Pharmacol 55(5):929–937

    CAS  PubMed  Google Scholar 

  17. Samimi G, Varki NM, Wilczynski S, Safaei R, Alberts DS, Howell SB (2003) Increase in expression of the copper transporter ATP7A during platinum drug-based treatment is associated with poor survival in ovarian cancer patients. Clin Cancer Res 9(16 Pt 1):5853–5859

    CAS  PubMed  Google Scholar 

  18. Komatsu M, Sumizawa T, Mutoh M, Chen ZS, Terada K, Furukawa T, Yang XL, Gao H, Miura N, Sugiyama T, Akiyama S (2000) Copper-transporting P-type adenosine triphosphatase (ATP7B) is associated with cisplatin resistance. Cancer Res 60(5):1312–1316

    CAS  PubMed  Google Scholar 

  19. Ishida S, Lee J, Thiele DJ, Herskowitz I (2002) Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc Natl Acad Sci USA 99(22):14298–14302

    Article  CAS  Google Scholar 

  20. Li X, Huang JM, Wang JN, Xiong XK, Yang XF, Zou F (2015) Combination of chrysin and cisplatin promotes the apoptosis of HepG2 cells by up-regulating p53. Chem Biol Interact 232:212–220

    Google Scholar 

  21. Inoue Y, Matsumoto H, Yamada S, Kawai K, Suemizu H, Gika M, Takanami I, Iwazaki M, Nakamura M (2010) Association of ATP7A expression and in vitro sensitivity to cisplatin in non-small cell lung cancer. Oncol Lett 1(5):837–840

    Article  CAS  Google Scholar 

  22. Li ZH, Qiu MZ, Zeng ZL, Luo HY, Wu WJ, Wang F, Wang ZQ, Zhang DS, Li YH, Xu RH (2012) Copper-transporting P-type adenosine triphosphatase (ATP7A) is associated with platinum resistance in non-small cell lung cancer (NSCLC). J Transl Med 10:21

    Article  Google Scholar 

  23. Yang T, Chen M, Chen T, Thakur A (2015) Expression of the copper transporters hCtr1, ATP7A and ATP7B is associated with the response to chemotherapy and survival time in patients with resected non-small cell lung cancer. Oncol Lett 10(4):2584–2590

    Article  CAS  Google Scholar 

  24. Gerke V, Creutz CE, Moss SE (2005) Annexins: linking Ca2+ signalling to membrane dynamics. Nat Rev Mol Cell Biol 6(6):449–461

    Article  CAS  Google Scholar 

  25. Han EK, Tahir SK, Cherian SP, Collins N, Ng SC (2000) Modulation of paclitaxel resistance by annexin IV in human cancer cell lines. Br J Cancer 83(1):83–88

    Article  CAS  Google Scholar 

  26. Wei R, Zhang Y, Shen L, Jiang W, Li C, Zhong M, Xie Y, Yang D, He L, Zhou Q (2012) Comparative proteomic and radiobiological analyses in human lung adenocarcinoma cells. Mol Cell Biochem 359(1–2):151–159

    Article  CAS  Google Scholar 

  27. Kim A, Enomoto T, Serada S, Ueda Y, Takahashi T, Ripley B, Miyatake T, Fujita M, Lee CM, Morimoto K, Fujimoto M, Kimura T, Naka T (2009) Enhanced expression of Annexin A4 in clear cell carcinoma of the ovary and its association with chemoresistance to carboplatin. Int J Cancer 125(10):2316–2322

    Article  CAS  Google Scholar 

  28. Matsuzaki S, Enomoto T, Serada S, Yoshino K, Nagamori S, Morimoto A, Yokoyama T, Kim A, Kimura T, Ueda Y, Fujita M, Fujimoto M, Kanai Y, Kimura T, Naka T (2014) Annexin A4-conferred platinum resistance is mediated by the copper transporter ATP7A. Int J Cancer 134(8):1796–1809

    Article  CAS  Google Scholar 

Download references

Funding

This study was funded by the Medical Science Research Key Project in HeBei province, China (no. ZD20140167).

Author information

Authors and Affiliations

  1. Department of Pharmacy, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China

    Mao Dong Zheng, Juan Yan, Jian Hua Tang & Xiu Hua Zhao

  2. Department of Pharmacy, Ji Nan Hospital, Jinan, Shandong, China

    Nai Dong Wang

  3. Yidu Central Hospital, Weifang, Shangdong, China

    Xiao Liang Li

  4. Department of Respiration, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China

    Zhihua Zhang

Authors
  1. Mao Dong Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nai Dong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao Liang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juan Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian Hua Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiu Hua Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhihua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhihua Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, M.D., Wang, N.D., Li, X.L. et al. Toosendanin mediates cisplatin sensitization through targeting Annexin A4/ATP7A in non-small cell lung cancer cells. J Nat Med 72, 724–733 (2018). https://doi.org/10.1007/s11418-018-1211-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11418-018-1211-0

Keywords

Search

Navigation