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Diallyl disulfide synergizes with melphalan to increase apoptosis and DNA damage through elevation of reactive oxygen species in multiple myeloma cells

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Abstract

Diallyl disulfide (DADS), one of the main components of garlic, is well known to have anticancer effects on multiple cancers. However, its efficacy in treating multiple myeloma (MM) is yet to be determined. We explored the effects of DADS on MM cells and investigated the synergistic effects of DADS when combined with five anti-MM drugs, including melphalan, bortezomib, carfilzomib, doxorubicin, and lenalidomide. We analyzed cell viability, cell apoptosis, and DNA damage to determine the efficacy of DADS and the drug combinations. Our findings revealed that DADS induces apoptosis in MM cells through the mitochondria-dependent pathway and increases the levels of γ-H2AX, a DNA damage marker. Combination index (CI) measurements indicated that the combination of DADS with melphalan has a significant synergistic effect on MM cells. This was further confirmed by the increases in apoptotic cells and DNA damage in MM cells treated with the two drug combinations compared with those cells treated with a single drug alone. The synergy between DADS and melphalan was also observed in primary MM cells. Furthermore, mechanistic investigations showed that DADS decreases reduced glutathione (GSH) levels and increases reactive oxygen species (ROS) production in MM cells. The addition of GSH is effective in neutralizing DADS cytotoxicity and inhibiting the synergy between DADS and melphalan in MM cells. Taken together, our study highlights the effectiveness of DADS in treating MM cells and the promising therapeutic potential of combining DADS and melphalan for MM treatment.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank Professor Wen Zhou from Central South University School of Basic Medical Sciences for providing MM cell lines.

Funding

This work was supported by grants from the Natural Science Foundation of Hunan Province (2023JJ10036), PhD Scientific Research Start-up Fund of the University of South China (200XQD075), Scientific Research Project of Hunan Department of Education (22B0452), Hunan Provincial Innovation Foundation for Postgraduates (CX20220975), and National College Student Innovation and Entrepreneurship Training Program (210XCX536, 220XCX079, 220XCX254, 220XCX486).

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Author notes

  1. Wei Hu, Jingqi Sun, and Yanyan Zhang contributed equally to this study.

Authors and Affiliations

  1. Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Changshengxi Road 28#, Hengyang, 421001, Hunan, China

    Wei Hu, Jingqi Sun, Yanyan Zhang, Ting Chen, Fen He, Hongyan Zhao, Weihong Tan, Zhijian Wang, Jiaqi Ouyang, Zhanyou Tang, Jiarui He, Jiayu Wang, Xi Zeng & Jiliang Xia

  2. Department of Hematology, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, Hunan, China

    Junjun Li

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  1. Wei Hu
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Contributions

J.X., X.Z., and J.L. designed the research. W.H., J.S., Y.Z., F.H., and T.C. performed the experiments and analyzed the data. H.Z., W. T., Z.W., J.O., Z.T., J.H., and J.W. provided technical assistance. J.X. and X.Z. wrote and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Junjun Li, Xi Zeng or Jiliang Xia.

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Hu, W., Sun, J., Zhang, Y. et al. Diallyl disulfide synergizes with melphalan to increase apoptosis and DNA damage through elevation of reactive oxygen species in multiple myeloma cells. Ann Hematol 103, 1293–1303 (2024). https://doi.org/10.1007/s00277-023-05592-w

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