title: Synergistic combination therapy with cotylenin A and vincristine in multiple myeloma models.
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.
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Tsutomu
authors: T
authors: Takahashi
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Yoshio
authors: Y
authors: Honma
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Takaaki
authors: T
authors: Miyake
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Koji
authors: K
authors: Adachi
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Saki
authors: S
authors: Takami
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Masahiro
authors: M
authors: Okada
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Satoshi
authors: S
authors: Kumanomidou
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Fumiyoshi
authors: F
authors: Ikejiri
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Yumi
authors: Y
authors: Jo
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Chie
authors: C
authors: Onishi
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Koshi
authors: K
authors: Kawakami
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Ichiro
authors: I
authors: Moriyama
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Masaya
authors: M
authors: Inoue
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Junko
authors: J
authors: Tanaka
authors: Department of Oncology/Hematology, Shimane University Hospital, Izumo-shi, Shimane, Japan.
authors: Junji
authors: J
authors: Suzumiya
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000008:administration & dosage* / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D014750:Vincristine / Q000008:administration & dosage* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C423222:cotylenin A; D014750:Vincristine