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. 2022 Jul 8;10(7):1638.
doi: 10.3390/biomedicines10071638.

Emodin Ameliorates the Efficacy of Carfilzomib in Multiple Myeloma Cells via Apoptosis and Autophagy

Chin-Mu Hsu  1 , Chia-Hung Yen  2   3 , Shu-Chen Wang  4 , Yi-Chang Liu  1   5 , Chien-Tzu Huang  1 , Min-Hong Wang  1 , Tzer-Ming Chuang  1 , Ya-Lun Ke  1 , Tsung-Jang Yeh  1 , Yuh-Ching Gau  1   6 , Jeng-Shiun Du  1   6 , Hui-Ching Wang  1   5   6 , Shih-Feng Cho  1   5 , Yuhsin Tsai  7 , Chi-En Hsiao  1 , Samuel Yien Hsiao  8 , Hui-Hua Hsiao  1   3   5   9
Affiliations

Emodin Ameliorates the Efficacy of Carfilzomib in Multiple Myeloma Cells via Apoptosis and Autophagy

Chin-Mu Hsu et al. Biomedicines. .

Abstract

Background: Carfilzomib, the proteasome inhibitor, can increase the overall survival rate of multiple myeloma (MM) patients undergoing targeted therapy. However, relapse and toxicity present great challenges for such treatment, so an urgent need for effective combination therapy is necessary. Emodin is a natural chemical compound that inhibits the proliferation of various cancers and can effectively combine with other treatments. In this study, we evaluated the sensitizing effect of emodin combined with carfilzomib on MM cells.

Methods: The cells were treated with emodin, carfilzomib, and a combination of drugs to determine their effects on cell proliferation and viability. The cell cycle distribution and reactive oxygen species (ROS) expression were measured by flow cytometry. The level of RNA and protein were analyzed through real-time qPCR and immunoblotting.

Results: Emodin acted synergistically with carfilzomib to reduce the proliferation and viability of MM cell lines in vitro. Furthermore, the combination of emodin and carfilzomib increased ROS production, inducing apoptosis and autophagy pathways via caspase-3, PARP, p62, and LC3B.

Conclusions: These results provide a molecular target for combination therapy in MM patients.

Keywords: apoptosis; autophagy; carfilzomib; cell cycle; emodin; p62; reactive oxygen species (ROS).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The structure of emodin and carfilzomib.
Figure 2
Figure 2
Cell viability of emodin (Emo), carfilzomib (CFZ), and combination drug of emodin and carfilzomib (E + C). (a) MM1S, H929, U266, and RPMI8226 cells were treated with various concentrations of CFZ for 72 h. (b) MM cells were treated with different emo concentrations for 72 h. (c) Emo (30 μM) enhanced the CFZ (5 nM) induced cytotoxicity to MM cells. * p < 0.05; ** p < 0.01; *** p < 0.001.
Figure 3
Figure 3
Differential cell cycle arrest with carfilzomib (CFZ), emodin (Emo) or combination drug of emodin and carfilzomib (E + C) for 24 h in MM cells. * p < 0.05; ** p < 0.01; *** p < 0.001.
Figure 4
Figure 4
Carfilzomib (CFZ), emodin (Emo), or combination drug of emodin and carfilzomib (E + C) increased ROS production in MM cells.
Figure 5
Figure 5
The combination therapy of carfilzomib (CFZ) and emodin (Emo) causes apoptosis in MM cells. The cells were incubated with CFZ (5 nM), Emo (30 μM), or the combination (E + C) for 24 h. * p < 0.05; ** p < 0.01; *** p < 0.001.
Figure 6
Figure 6
Carfilzomib (CFZ) and emodin (Emo) combination treatment modulated autophagy pathway. CFZ (5 nM), Emo (30 μM) and combination (E + C) treated MM1S and H929 for 24 h. (a) Relative RNA expression in BECN1 and LC3A; (b) The protein level of p62 and LC3B were detected by immunoblotting. * p < 0.05; ** p < 0.01; *** p < 0.001.
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