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Published on: May 15, 2019
Parthenolide-induced apoptosis in multiple myeloma cells involves reactive oxygen species generation and cell
Wei Wang1, Masaaki Adachi, Rina Kawamura
1Division of Molecular Oncology and Molecular Diagnosis, Graduate School of Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo, 060-8543, Japan.
Abstract:
The sesquiterpene lactone, parthenolide (PTL), possesses strong anticancer activity against various cancer cells. We report that PTL strongly induced apoptosis in 4 multiple myeloma (MM) cell lines and primary MM cells (CD38(+) high), but barely induced death in normal lymphocytes (CD38(-/+)low). PTL-mediated apoptosis correlated well with ROS generation and was almost completely inhibited by L-N-acetylcysteine (L-NAC), indicating the crucial role of oxidative stress in the mechanism. Among 4 MM cell lines, there is considerable difference in susceptibility to PTL. KMM-1 and MM1S cells sensitive to PTL possess less catalase activity than the less sensitive KMS-5 and NCI-H929 cells as well as normal lymphocytes. A catalase inhibitor 3-amino-1,2,4-triazole enhanced their PTL-mediated ROS generation and cell death. The siRNA-mediated knockdown of catalase in KMS-5 cells decreased its activity and sensitized them to PTL. Our findings indicate that PTL induced apoptosis in MM cells depends on increased ROS and intracellular catalase activity is a crucial determinant of their sensitivity to PTL.
Insights
Parthenolide (PTL) induces cancer cell death through oxidative stress. Intracellular catalase levels determine multiple myeloma cell sensitivity to PTL, offering a potential therapeutic target.
Area of Science:
- Biochemistry
- Oncology
- Cell Biology
Background:
- Parthenolide (PTL), a sesquiterpene lactone, exhibits potent anticancer properties.
- Multiple myeloma (MM) is a cancer of plasma cells, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the mechanism of PTL-induced apoptosis in multiple myeloma cells.
- To identify factors influencing differential sensitivity of MM cells to PTL.
Main Methods:
- Treatment of MM cell lines and primary MM cells with PTL.
- Assessment of apoptosis, reactive oxygen species (ROS) generation, and catalase activity.
- Inhibition of ROS with L-N-acetylcysteine (L-NAC) and catalase inhibition/knockdown.
Main Results:
- PTL induced apoptosis in MM cells, correlating with increased ROS generation.
- Normal lymphocytes were less sensitive to PTL compared to MM cells.
- Lower catalase activity in sensitive MM cell lines (KMM-1, MM1S) compared to less sensitive ones (KMS-5, NCI-H929) and normal lymphocytes.
- Catalase inhibition or knockdown sensitized MM cells to PTL-induced cell death.
Conclusions:
- PTL-induced apoptosis in MM cells is mediated by ROS.
- Intracellular catalase activity is a key determinant of MM cell sensitivity to PTL.
- Targeting catalase may enhance the efficacy of PTL in multiple myeloma treatment.
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