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Am J Cancer Res. 2018 Jan 1;8(1):16-29. eCollection 2018.

cAMP induces cell apoptosis in multiple myeloma and overcomes bortezomib resistance.

Author information

1
Department of Hematology, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200011, P. R. China.
2
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology, Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of The Chinese Ministry of Education Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025, P. R. China.

Abstract

The acquired resistance to bortezomib represents a major obstacle for multiple myeloma (MM) treatment. Studies revealed that the treatment with cyclic adenosine monophosphate (cAMP) may be a promising strategy for MM therapy. Therefore, the present study aimed to explore the mechanism of action of cAMP in MM cells. Our results showed that 8-CPT-cAMP and bortezomib synergistically induced growth inhibition and apoptosis in MM bortezomib-resistant cell lines and primary MM cells, in which protein kinase A (PKA) activation was involved. Furthermore, 8-CPT-cAMP induced the degradation of cyclinD1 and downregulation of myeloid cell leukemia-1 (Mcl-1). Moreover, 8-CPT-cAMP enhanced endoplasmic reticulum stress caused by bortezomib. A synergy between bortezomib and cAMP was also revealed in a murine MOPC315 xenograft model, which was evidenced by the significantly inhibited tumor growth and the improved multiple cancer-related parameters by the combination of the cAMP-elevating compound forskolin and bortezomib. Taken together, this study suggests that the treatment with cAMP may be a promising strategy for enhancing the therapeutic efficacy of bortezomib in MM treatment.

KEYWORDS:

Multiple myeloma; apoptosis; bortezomib; cAMP

PMID:
29416917
PMCID:
PMC5794718

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