Synergistic combination therapy with cotylenin A and vincristine in multiple myeloma models

Abstract

Abstract. Multiple myeloma is a malignant proliferative disease of plasma cells in the bone marrow and remains largely incurable. Cotylenin A, a fusicoccane diterpene glycoside with a complex sugar moiety, was isolated as a plant-growth regulator. Cotylenin A has been shown to inhibit the growth of various cancer cells. Herein, we examined the anti-myeloma effects of cotylenin A using five human myeloma cell lines (RPMI-8226, KMS-11, KMS-26, KMS-12 PE and KMS-12 BM) and xenografts in immunodeficient mice. Cotylenin A and vincristine synergistically inhibited the growth and induced apoptosis in myeloma cells. While other microtubule-disturbing agents also showed co-operative effects with cotylenin A, other anticancer agents, such as doxorubicin, cisplatin, camptothecin, methotrexate, gemcitabine and 5-fluorouracil, did not show such co-operation with cotylenin A. These differences might be attributed to the effects on autophagic responses. Combined treatment with cotylenin A and vincristine induced autophagy (formation of LC3-II and degradation of p62 protein). However, doxorubicin did not enhance the autophagy induced by cotylenin A. A colony-forming assay indicated that the combined treatment with cotylenin A and vincristine more effectively suppressed the formation of large colonies, which have higher self-renewal activity than vincristine alone. Expression of pluripotency-associated transcription factor Sox2 mRNA in RPMI-8226 myeloma cells was significantly suppressed by treatment with cotylenin A. Combined treatment with cotylenin A and vincristine significantly inhibited the growth of KMS-26 myeloma cells as xenografts. Our results suggest that the combination of cotylenin A and vincristine may have therapeutic value. Recently, it was reported that cotylenin A modulates the 14-3-3 intracellular signaling pathway. The 14-3-3 proteins may be novel targets in treating myeloma.However, our study could not explain how the sensitization to vincristine is related to the effects of cotylenin A on the 14-3-3 signaling pathway and further studies will be needed.

Modulators of Protein–Protein Interactions

“…146,147 Interestingly, anticancer properties were found by combining 22 with other agents such as vincristine. 148 The crystal structure of 22 bound to a complex of 14-3-3 with the N-terminal binding motifs of the protein kinase C-Raf published in 2013 gave important structural insight into how 22 can mediate its antitumor activity. 149 The 5-8-5-fused ring system of the fusicoccane scaffold is highly complex, and thus, investigating structural variation in the search for selectivity or enhanced potency is challenging.…”

Clotam enhances anti-proliferative effect of vincristine in Ewing sarcoma cells

“…Previously, VCR treatment was shown to upregulate survivin protein expression in chromic myeloid leukemia cells (39). However, recent report suggests that VCR enhanced the anti-cancer activity of Cotylenin A partially by inhibiting expression of anti-apoptotic proteins, cellular inhibitor of apoptosis protein (cIAP), and Survivin (40). Survivin regulates G2/M cell cycle phase transition (41).…”

Modulators of 14-3-3 Protein–Protein Interactions

“… 146 , 147 Interestingly, anticancer properties were found by combining 22 with other agents such as vincristine. 148 The crystal structure of 22 bound to a complex of 14-3-3 with the N-terminal binding motifs of the protein kinase C-Raf published in 2013 gave important structural insight into how 22 can mediate its antitumor activity. 149 …”