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6-Methoxydihydrosanguinarine exhibits cytotoxicity and sensitizes TRAIL-induced apoptosis of hepatocellular carcinoma cells through ROS-mediated upregulation of DR5

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Abstract

6-methoxydihydrosanguinarine (6-MS), a natural benzophenanthridine alkaloid extracted from Macleaya cordata (Willd.) R. Br, has shown to trigger apoptotic cell death in cancer cells. However, the exact mechanisms involved have not yet been clarified. The current study reveals the underlying mechanisms of 6-MS-induced cytotoxicity in hepatocellular carcinoma (HCC) cells and investigates whether 6-MS sensitizes TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis. 6-MS was shown to suppress cell proliferation and trigger cell cycle arrest, DNA damage, and apoptosis in HCC cells. Mechanisms analysis indicated that 6-MS promoted reactive oxygen species (ROS) generation, JNK activation, and inhibits EGFR/Akt signaling pathway. DNA damage and apoptosis induced by 6-MS were reversed following N-acetyl-l-cysteine (NAC) treatment. The enhancement of PARP cleavage caused by 6-MS was abrogated by pretreatment with JNK inhibitor SP600125. Furthermore, 6-MS enhanced TRAIL-mediated HCC cells apoptosis by upregulating the cell surface receptor DR5 expression. Pretreatment with NAC attenuated 6-MS-upregulated DR5 protein expression and alleviated cotreatment-induced viability reduction, cleavage of caspase-8, caspase-9, and PARP. Overall, our results suggest that 6-MS exerts cytotoxicity by modulating ROS generation, EGFR/Akt signaling, and JNK activation in HCC cells. 6-MS potentiates TRAIL-induced apoptosis through upregulation of DR5 via ROS generation. The combination of 6-MS with TRAIL may be a promising strategy and warrants further investigation.

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Acknowledgements

We thank all the contributors of the public databases used in this study

Funding

This work was supported by the Shandong Provincial Natural Science Foundation, China (No ZR2022MH178); Project of Administration of Traditional Chinese Medicine of Shandong Province, China (No 2020M064); Science and Technology Innovation Project of Taian (No 2022NS353). Natural Science Foundation of Shandong Province, ZR2022MH178, Feng-ze Wang ,Science and Technology Innovation Project of Taian, 2022NS353, lu cao , Project of Administration of Traditional Chinese Medicine of Shandong Province, 2020M064, Gang-ping Hao

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  1. Lin-lin Wang and Ruo-tong Li have contributed equally to this work.

Authors and Affiliations

  1. School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, People’s Republic of China

    Lin-lin Wang, Zi-heng Zang, Yun-xuan Song, Yu-zhe Zhang, Teng-fei Zhang, Feng-ze Wang & Gang-ping Hao

  2. Department of Pathology, Tai’ an Central Hospital, Taian, 271000, People’s Republic of China

    Ruo-tong Li

  3. Department of Pathology, The Second Affiliated Hospital of Shandong First Medical University, Taian, 271000, People’s Republic of China

    Feng-ze Wang & Lu Cao

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Contributions

LW and RL: Conceptualization, draft preparation, investigation. ZZ and YS: data curation and investigation. YZ and TZ: investigation. FW: validation. GH: Funding acquisition and writing—editing. LC: Funding acquisition, writing—reviewing and editing. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

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Correspondence to Gang-ping Hao or Lu Cao.

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Wang, Ll., Li, Rt., Zang, Zh. et al. 6-Methoxydihydrosanguinarine exhibits cytotoxicity and sensitizes TRAIL-induced apoptosis of hepatocellular carcinoma cells through ROS-mediated upregulation of DR5. Med Oncol 40, 266 (2023). https://doi.org/10.1007/s12032-023-02129-z

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