Stabilization of Physical RAF/14-3-3 Interaction by Cotylenin A as Treatment Strategy for RAS Mutant Cancers

Molzan, Manuela; Kasper, Stefan; Röglin, Lars; Skwarczynska, Malgorzata; Sassa, Takeshi; Inoue, Takatsugu; Breitenbuecher, Frank; Ohkanda, Junko; Kato, Nobuo; Schüler, Martin; Ottmann, C.

doi:10.1021/cb4003464

Cited by 108 publications

(124 citation statements)

References 18 publications

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“…Cotylenin A co-operatively inhibited tumor growth in xenografts with IFNα (6), rapamycin (9) or cetuximab (31). Treatment with cotylenin A had no apparent adverse effects on mice, and reduced the adverse effects of vincristine on tumor-bearing mice.…”

Section: Discussionmentioning

confidence: 98%

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

Takahashi

Honma

Miyake

et al. 2015

International Journal of Oncology

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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.

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Section: Discussionmentioning

confidence: 98%

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

Takahashi

Honma

Miyake

et al. 2015

International Journal of Oncology

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“…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. Nevertheless, structure-based design and semisynthesis have enabled the discovery of potent analogues.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Modulators of Protein–Protein Interactions

et al. 2014

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Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein−protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as "undruggable" targets, the last two decades have seen an increasing number of successful examples of PPI modulators, resulting in growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This perspective focuses on the hub-protein 14-3-3, which has several hundred identified protein interaction partners, and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products.

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“…For example, fusicoccin A shows antitumor activity [52], promotes platelet aggregation [53] and stabilizes the inhibitory binding of 14-3-3 to ERa [54]. Cotylenin A has been shown to induce differentiation in myeloid leukemia [55], display activity against breast cancer cells [56] and stabilize the inhibitory binding of 14-3-3 proteins to c-Raf [57,58]. We have furthermore shown that a semisynthetic derivative of fusicoccin -FC-THF -enhances transport of the potassium channel TASK3 to the plasma membrane by stabilizing 14-3-3 binding to the C terminus of TASK3 [59].…”

Section: Forskolinmentioning

confidence: 99%