Journal of Natural Medicines

, Volume 72, Issue 3, pp 724–733 | Cite as

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

  • Mao Dong Zheng
  • Nai Dong Wang
  • Xiao Liang Li
  • Juan Yan
  • Jian Hua Tang
  • Xiu Hua Zhao
  • Zhihua ZhangEmail author
Original Paper


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.


Toosendanin Non-small cell lung cancer cells Cisplatin sensitization Annexin A4 



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

Compliance with ethical standards

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.


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Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Mao Dong Zheng
    • 1
  • Nai Dong Wang
    • 2
  • Xiao Liang Li
    • 3
  • Juan Yan
    • 1
  • Jian Hua Tang
    • 1
  • Xiu Hua Zhao
    • 1
  • Zhihua Zhang
    • 4
    Email author
  1. 1.Department of PharmacyThe First Affiliated Hospital of Hebei North UniversityZhangjiakouChina
  2. 2.Department of PharmacyJi Nan HospitalJinanChina
  3. 3.Yidu Central HospitalWeifangChina
  4. 4.Department of RespirationThe First Affiliated Hospital of Hebei North UniversityZhangjiakouChina

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