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The antitumor effect of the novel agent MCL/ACT001 in pancreatic ductal adenocarcinoma

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Abstract

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is a major challenge in cancer therapy, there are more than four hundred thousand deaths per year, and the 5-year survival rate is less than 10%. The incidence continues to rise. Treatment with classic drugs offers limited therapeutic benefits. The aim of this study was to investigate the mechanism and effect of the new agent ACT001, the active metabolite of Micheliolide (MCL), in vitro and in vivo against PDAC.

Methods

MTT assay, wound healing assay, and flow cytometry were used to assess the effects of MCL/ACT001 in vitro. DCFH-DA assay was used to assess ROS accumulation. Western blotting, immunohistochemical staining and TUNEL assay were also conducted to determine the mechanisms. PANC-1-Luc cells and bioluminescent reporter imaging were used to assess antitumor effect of ACT001 using a orthotopic xenograft model in vivo.

Results

MCL/ACT001 significantly inhibited cell growth in PDAC in a dose-dependent manner, induced cell apoptosis, cell migration and reactive oxygen species (ROS) accumulation in vitro. In vivo, ACT001 (400 mg/kg/day) inhibited PDAC tumor growth in orthotopic xenograft mice. We verified that EGFR and Akt were markedly overexpressed in PDAC cells and patient tumors. Mechanistic investigations revealed that MCL exerted its antitumor activity via regulation of the EGFR–Akt–Bim signaling pathway, thus inducing Bim expression both in vitro and in vivo.

Conclusion

MCL/ACT001 is a highly promising agent in the treatment of PDAC patients.

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Data availability

All data generated that are relevant to the results presented in this article are included in this article. Other data that were not relevant for the results presented here are available from the corresponding author (C L) upon reasonable request.

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Funding

This work was financially supported by “The Fundamental Research Funds for the Central Universities (Nankai University, #ZB19100128)” to C L.

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Authors and Affiliations

  1. State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, No.38 Tongyan Road, Jinnan District, Tianjin, 300350, People’s Republic of China

    Juan Yang, Yin Li, Xiao Han, Xiaolin Pei, Zhoujun Lin & Chenggang Li

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  1. Juan Yang
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  2. Yin Li
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  3. Xiao Han
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  4. Xiaolin Pei
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  5. Zhoujun Lin
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Contributions

CL and JY designed this study, completed the data analysis, drafted all figures, and wrote the manuscript; JY, XH, YL and ZL performed the experiment, collected the data and revised the manuscript. XP participated in the animal experiment. All authors read and agree with the final manuscript. CL designed, supervised, and guided this study and revised the final manuscript.

Corresponding author

Correspondence to Chenggang Li.

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All authors declare no potential conflicts of interest.

Ethics statement

All animal studies were approved by the Institutional Animal Care and Use Committee at Nankai University. Human experiments were approved by the human experimentation committee and informed consent was obtained from all subjects.

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Yang, J., Li, Y., Han, X. et al. The antitumor effect of the novel agent MCL/ACT001 in pancreatic ductal adenocarcinoma. J Cancer Res Clin Oncol 149, 5717–5728 (2023). https://doi.org/10.1007/s00432-022-04542-9

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