1999

DOI: 10.1038/sj.bjc.6690327

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Vesnarinone and glucocorticoids cooperatively induce G1 arrest and have an anti-tumour effect on human non-small cell lung carcinoma cells grown in nude mice

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Yuri Yamamoto‐Yamaguchi

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,

Yasuhiro Kanatani

³

Abstract: Vesnarinone, an oral cardiotonic, inhibited the growth of several human non-small cell lung carcinoma cell lines, and its anti-proliferative effects in vitro and in vivo were greatly enhanced by combination with glucocorticoids, but not other steroids. Simultaneous treatment with vesnarinone and dexamethasone is the most effective to evoke the synergistic effect in the growth inhibition of lung carcinoma EBC-1 cells. Dexamethasone and other glucocorticoids induced morphological changes in EBC-1 cells and these… Show more

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-Piperazinyl]-2(1h)-quinolinone; Also Called Opc-82121

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Assessment Of Cell Cycle1

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Cited by 30 publications

(49 citation statements)

References 26 publications

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“…Combined treatment with IFNα and cotylenin A preferentially induced apoptosis in human lung cancer cells while sparing normal lung epithelial cells and significantly inhibited the growth of human lung cancer cells as xenografts without apparent adverse effects, suggesting that this combination may have therapeutic value in treating human cancer (5)(6)(7). These findings suggest that cotylenin A may be useful in the therapy for leukemia and some other malignancies.…”

Section: Introductionmentioning

confidence: 74%

“…We treated mice with cotylenin A at 5 mg/kg body weight, as described previously (4,6). This dose of cotylenin A was well-tolerated without a loss of body weight.…”

Section: Effects Of Cotylenin a And Vincristine On In Vivo Growth Of mentioning

confidence: 99%

See 1 more Smart Citation

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

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²

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³

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.

“…Combined treatment with IFNα and cotylenin A preferentially induced apoptosis in human lung cancer cells while sparing normal lung epithelial cells and significantly inhibited the growth of human lung cancer cells as xenografts without apparent adverse effects, suggesting that this combination may have therapeutic value in treating human cancer (5)(6)(7). These findings suggest that cotylenin A may be useful in the therapy for leukemia and some other malignancies.…”

Section: Introductionmentioning

confidence: 74%

“…We treated mice with cotylenin A at 5 mg/kg body weight, as described previously (4,6). This dose of cotylenin A was well-tolerated without a loss of body weight.…”

Section: Effects Of Cotylenin a And Vincristine On In Vivo Growth Of mentioning

confidence: 99%

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

¹

,

²

,

³

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.

“…In addition, vesnarinone has been shown to inhibit the production of HIV-1 (20) and reduces the lethality of endotoxemia (21). Besides immunomodulatory effects, vesnarinone has been found to suppress the growth of a wide variety of tumor cell lines, including those derived from human gastric cancer (22,23), lung cancer (24,25), hepatocellular carcinoma (26), adenoid squamous carcinoma (27,28), glioma (29), acute myeloid leukemia (30,31), and prostate cancer (32).…”

Section: -Piperazinyl]-2(1h)-quinolinone; Also Called Opc-8212mentioning

confidence: 99%

Vesnarinone Suppresses TNF-Induced Activation of NF-κB, c-Jun Kinase, and Apoptosis

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²

2000

The Journal of Immunology

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Vesnarinone, a synthetic quinolinone derivative used in the treatment of cardiac failure, exhibits immunomodulatory, anti-inflammatory, and cell growth regulatory properties. The mechanisms underlying these properties are not understood, but due to the critical role of nuclear transcription factor NF-κB in these responses, we hypothesized that vesnarinone must modulate NF-κB activation. We investigated the effect of vesnarinone on NF-κB activation induced by inflammatory agents. Vesnarinone blocked TNF-induced activation of NF-κB in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of IκBα, an inhibitor of NF-κB. The effects of vesnarinone were not cell type specific, as it blocked TNF-induced NF-κB activation in a variety of cells. NF-κB-dependent reporter gene transcription activated by TNF was also suppressed by vesnarinone. The TNF-induced NF-κB activation cascade involving TNF receptor 1-TNF receptor associated death domain-TNF receptor associated factor 2 NF-κB-inducing kinase-IKK was interrupted at the TNF receptor associated factor 2 and NF-κB-inducing kinase sites by vesnarinone, thus suppressing NF-κB reporter gene expression. Vesnarinone also blocked NF-κB activation induced by several other inflammatory agents, inhibited the TNF-induced activation of transcription factor AP-1, and suppressed the TNF-induced activation of c-Jun N-terminal kinase and mitogen-activated protein kinase kinase. TNF-induced cytotoxicity, caspase activation, and lipid peroxidation were also abolished by vesnarinone. Overall, our results indicate that vesnarinone inhibits activation of NF-κB and AP-1 and their associated kinases. This may provide a molecular basis for vesnarinone’s ability to suppress inflammation, immunomodulation, and growth regulation.

“…The cell-cycle analysis procedure was previously described (Honma et al, 1999). Briefly, after 5 days of culture in PRF-RPMI with 10% DCC-FCS or RPMI with 10% FCS, the cells had grown to less than 60% confluency, and were then washed in ice-cold PBS, fixed by the addition of 70% ethanol and left for 30 min on ice.…”

Section: Assessment Of Cell Cyclementioning

confidence: 99%

Estrogen receptor (ER) β1 and ERβcx/β2 inhibit ERα function differently in breast cancer cell line MCF7

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,

²

,

Yamamoto‐Yamaguchi

³

et al. 2003

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Estrogen receptor (ER) a plays an important role in the proliferation and progression of breast cancer. In order to explore the function of wild-type ERb (ERb1) and its variant form, ERbcx/b2, stable transformants of ERapositive breast cancer MCF7 cells with ERb1 or ERbcx/ b2 expression vector were established. Constitutive expression of ERb1 or ERbcx/b2 reduced the S phase population of the cell cycle in dish culture and the number of colonies in an anchorage-independent assay. DNAprotein complexes of ERE with nuclear extracts from ERb1 transformants were observed in the electrophoretic mobility shift assay, while no complex was observed for ERbcx/b2 transformants. Reporter gene assay using estrogen-responsive element (ERE)-luciferase showed less responsiveness to estrogen in these transformants compared with parental cells. Endogenous mRNA expression of two known estrogen-responsive genes, cathepsin D and IGFBP4, was weakly induced by estrogen in ERb1 and ERbcx/b2 transformants compared with parental cells. A comprehensive gene expression analysis using our custommade cDNA microarray showed that MCF7 and ERb1 transformants had a similar gene expression profile, whereas ERbcx/b2 showed a distinct profile from others. These results indicate that ERb1 and ERbcx/b2 inhibit ERa function differently in MCF7 cells.

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