2. Academic Validation
  3. Doxorubicin-mediated retardation of aggresome formation enhances Carfilzomib-induced cell death synergistically by augmenting ER stress and proapoptotic signaling

Doxorubicin-mediated retardation of aggresome formation enhances Carfilzomib-induced cell death synergistically by augmenting ER stress and proapoptotic signaling

  • Eur J Pharmacol. 2025 Dec 5:1008:178303. doi: 10.1016/j.ejphar.2025.178303.
Chang-Tze Ricky Yu 1,  Yu-Ting Amber Liao 1,  Hsin-Yu Bella Pan 1,  Jo-Mei Maureen Chen 1,  Chia-Yun Pan 1,  Chi-Yin Nina Chiang 1,  Jia-Rung Tsai 2,  Kuo-Hsuan Hsu 3,  Chieh-Lin Jerry Teng 4
Affiliations

Affiliations

  • 1 Department of Applied Chemistry, National Chi Nan University, No 1, University Road Puli, Nantou, 54561, Taiwan.
  • 2 Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, No. 1650 Taiwan Boulevard Sect. 4, Taichung, 40705, Taiwan.
  • 3 Department of Chest Medicine, Taichung Veterans General Hospital, No. 1650 Taiwan Boulevard Sect. 4, Taichung, Taiwan, 40705; Lung Cancer Comprehensive Care and Research Center, Taichung Veterans General Hospital, No. 1650 Taiwan Boulevard Sect. 4, Taichung, Taiwan, 40705.
  • 4 Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, No. 1650 Taiwan Boulevard Sect. 4, Taichung, 40705, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, No. 145 Xingda Rd., South Dist, Taichung, 40202, Taiwan; Ph.D. Program in Translational Medicine, National Chung Hsing University, No. 145 Xingda Rd., South Dist, Taichung, 40202, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, No. 145 Xingda Rd., South Dist, Taichung, 40202, Taiwan; School of Medicine, Chung Shan Medical University, No. 110, Section 1, Jianguo North Road, Taichung, 40201, Taiwan. Electronic address: [email protected].
PMID: 41183585 DOI: 10.1016/j.ejphar.2025.178303
Abstract

Multiple myeloma (MM), the second most common hematological malignancy, is associated with anemia, renal dysfunction, bone pain, and hypercalcemia. Proteasome inhibitors are a mainstay in MM therapy, but resistance, often mediated by aggresome formation, remains a challenge. Aggresomes sequester misfolded proteins and facilitate their clearance via Autophagy. This study focused on identifying Anticancer agents that inhibit aggresome formation in response to carfilzomib and exploring their mechanisms of action. We employed MM cell lines U266B1, LP-1, RPMI-8266, and NCI-H929, assessing cell viability using Trypan blue and aggresome structures through immunofluorescence. We quantified protein levels of aggresome regulators, ER and Golgi stress markers, and pro-apoptotic factors using western blotting. Results indicated that doxorubicin significantly enhances carfilzomib-induced cell death and disrupts aggresome formation in U266B1 cells. Mechanistic analyses revealed that doxorubicin downregulated structural components and promotors of aggresome formation, including Vimentin, HDAC6, p62, HSP70, BAG3, HOOK2, and Dynein. Furthermore, doxorubicin potentiated carfilzomib-induced MM cell death by enhancing ER and Golgi stress responses and promoting Apoptosis. Notably, doxorubicin did not potentiate Proteasome inhibitor-mediated MM cell death in the absence of aggresome-inducing activity. Combined treatment with carfilzomib and doxorubicin failed to induce synergistic cell death in three MM cell lines (LP-1, RPMI-8266, and NCI-H929) lacking aggresome-forming capability, which exhibited higher sensitivity to carfilzomib than U266B1 cells. In conclusion, our findings suggest that doxorubicin enhances carfilzomib-induced cell death by inhibiting aggresome formation and that the combined treatment with carfilzomib and doxorubicin may be an effective strategy to target MM cells with aggresome-forming activity.

Keywords

Carfilzomib; Doxorubicin; ER; Golgi; Myeloma; aggresome.

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