Cyclin D1 Overexpression and Response to Bortezomib Treatment in a Breast Cancer Model

Ishii, Yuki; Pirkmaier, Andreja; Alvarez, James V.; Frank, David A.; Keselman, Inna; Logothetis, Diomedes E.; Mandeli, John; O’Connell, Matthew J.; Waxman, Samuel; Germain, Doris

doi:10.1093/jnci/djj334

Cited by 58 publications

(46 citation statements)

References 36 publications

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“…Significant data concerning miRNA in MM have been reported only recently by various groups, showing signatures associated with specific molecular types and suggesting that distinct miRNAs may play an important role in neoplastic transformation and disease progression [151][152][153][154]. Experimental data have also recently suggested that miRNA-15a and miRNA-16, which are located in the 13q14 region, frequently deleted in MM, may play a role in MM cell proliferation, representing promising targets for novel therapies [155]. Novel prognostic tools are also being extensively explored, and cyclins functioning as cell cycle regulators have proved to be of interest, since overexpression of the cyclin genes CCND1, 2, and 3 are recurring abnormalities in human cancer.…”

Section: Conclusion and Perspectives Toward The Road To Cure MMmentioning

confidence: 99%

Consensus statement from European experts on the diagnosis, management, and treatment of multiple myeloma: from standard therapy to novel approaches

Engelhardt

Kleber

Udi

et al. 2010

Leukemia & Lymphoma

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Original Citation:Consensus statement from European experts on the diagnosis, management, and treatment of multiple myeloma: from standard therapy to novel approaches. Terms of use:Open Access (Article begins on next page) Anyone can freely access the full text of works made available as "Open Access". Works made available under a Creative Commons license can be used according to the terms and conditions of said license. Use of all other works requires consent of the right holder (author or publisher) if not exempted from copyright protection by the applicable law. Availability: This is the author's manuscriptThis version is available http://hdl.handle.net/2318/81898 since This is an author version of the contribution published on: Questa è la versione dell'autore dell'opera: [August 2010, Vol. 51, No. 8 , Pages 1424-1443 (doi:10.3109/10428194.2010 ABSTRACTTreatment for multiple myeloma (MM) has changed beyond recognition over the past two decades. During the early 1980s, MM inevitably resulted in a slow progressive decline in quality of life until death after about 2 years, while today patients can expect a 50% chance of achieving a complete remission, median survival of 5 years, and a 20% chance of surviving longer than 10 years. An international expert opinion meeting (including members of the GIMEMA and DSMM study groups) was held in 2009. One of the outcomes of the meeting was the development of a consensus statement outlining contemporary optimal clinical practice for the treatment of MM. The international panel recommended that the state of the art therapy for MM should comprise: (a) evidence-based supportive care, (b) effective and well-tolerated chemotherapeutic regimens, (c) autologous hematopoietic stem cell transplant (ASCT) for patients suitable for intensive conditioning therapy, and (d) evidence-based incorporation of novel anti-MM agents. Maintenance strategies have also become increasingly important for the prolongation of remission after front-line therapies. In addition, improved understanding of the biology of MM has led to the development of novel biological therapeutic agents such as thalidomide, lenalidomide, bortezomib, and others. These agents specifically target intracellular mechanisms and interactions, such as those within the bone marrow microenvironment, and have been integrated into MM treatment. This report reviews recent clinical advances in the treatment strategies available for MM and provides an overview of the state of the art management of patients with MM.

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Section: Conclusion and Perspectives Toward The Road To Cure MMmentioning

confidence: 99%

Consensus statement from European experts on the diagnosis, management, and treatment of multiple myeloma: from standard therapy to novel approaches

Engelhardt

Kleber

Udi

et al. 2010

Leukemia & Lymphoma

View full text Add to dashboard Cite

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“…Given that the cyclins are substrates of the proteasome, 25 we next examined MM cell cytotoxicity of P276-00 in combination with bortezomib. Increasing concentrations of P276-00 (0-1000 nM) were added with bortezomib (0-5 nM), and MM cell cytotoxicity was assayed by MTT at 24 h (Figure 5d).…”

Section: P276-00 Has Synergistic Anti-mm Activity When Combined With mentioning

confidence: 99%

“…Our data demonstrate that P276-00 overcomes the growth and survival advantage conferred by cytokines and BMSCs suggesting that it can overcome drug resistance. Given that the cyclins and Cdks are substrates of the proteasome, 25 and that proteasome inhibition may result in accumulation of these proteins conferring drug resistance, we combined bortezomib with P276-00. Our data demonstrate marked synergism of P276-00 with bortezomib.…”

Section: P276-00 Is Active In An MM Xenograft Modelmentioning

confidence: 99%

Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma

et al. 2009

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Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in 450% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclindependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspasedependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.

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“…Because of its pivotal role in promoting cell cycle progression and, hence, cell division and proliferation, such overexpression might be expected to coincide with poor prognosis. 30,31 Overexpression of cyclin D1 has also been linked to the development of endocrine resistance in breast cancer cells. 32 Cyclin D1 overexpression is a common event in cancer, but does not occur solely as a consequence of gene amplification.…”

Section: Expression Of Apoptosis Bcl-2 and Bax In Mammary Cancer Tismentioning

confidence: 99%

β‐Ionone suppresses mammary carcinogenesis, proliferative activity and induces apoptosis in the mammary gland of the Sprague‐Dawley rat

Liu

Sun

Dong

et al. 2008

Intl Journal of Cancer

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b-Ionone demonstrates potent anticancer activity both in vitro and in vivo. We determined tumor incidence and the number of rats bearing tumors as well as cell proliferation and apoptosis in a rat mammary cancer model induced by 7, 12-dimethylbenz[a]anthracene (DMBA). Rats were fed an AIN-76A diet containing b-ionone (0, 9, 18 or 36 mmol/kg), starting 2 weeks before DMBA administration and continuing for 24 weeks. A dose-dependent inhibition of mammary carcinogenesis by dietary b-ionone was observed. Corresponding tumor incidence values were 82.1, 53.3, 25.9 and 10.0% (p < 0.01 or 0.05). Time to tumor appearance increased and tumor multiplicity decreased with increasing dietary b-ionone. Histopathological and immunohistochemical evaluations of tumors were performed on the 64, 31, 15 and 3 tumors, respectively, identified in rats from the respective groups of 30. The proportions of adenocarcinomas, adenomas and benign masses were equally distributed in the latter group. In proportions within the other groups, the proportions of adenocarcinomas and benign masses decreased and increased with increasing dietary b-ionone. Proliferating cell nuclear antigen (PCNA), cyclin D1 and Bcl-2 expression decreased, and Bax expression and nuclear fragmentation increased with increasing dietary b-ionone. These results demonstrate the potent capacity of dietary b-ionone to suppress DMBA-initiated mammary cancer in rats. ' 2008 Wiley-Liss, Inc.Key words: b-ionone; mammary carcinogenesis; cell proliferation; apoptosis Epidemiological studies have generally shown that the consumption of vitamin-rich fruits, vegetables and whole grains is inversely associated with risks for cancer and other chronic diseases. [1][2][3][4] Failing to demonstrate an inverse relationship between cancer incidence and consumption of the vitamins prominent in these plant products, investigators have turned attention to the many classes of nutrient phytochemical constituents also present in these foods. 5 Specific isoprenoids, culled from a group of some 22,000 products of secondary plant metabolic pathways sharing a common precursor, mevalonic acid, 6 have demonstrated anticarcinogenic and chemoprotective activities. One phytochemical compound, b-ionone, an end ring analog of b-carotenoid, represents a subclass of cyclic isoprenoids. Physiological functions attributed to b-ionone include the inhibition of the growth of fungi 7 and the regulation of the synthesis of mevalonate-derived constituents. 8 In previous studies, b-ionone inhibited the growth of breast-, gastric-, colon-and HL-60-cancer cells in a dosedependent manner, 9-13 affected the MAPK pathway of MDA MB 435 cells, 14 and induced apoptosis of SGC-7901 gastric cancer cells and B16 murine tumor cells. 10,12 In addition, b-ionone could also affect metastasis in B16 and SGC-7901 cancer cell lines. 11,12,15 Dietary studies reveal the chemopreventive 16 and antitumor 17 activities of b-ionone.This study confirms and extends observations of the chemopreventive impact of, and actions triggered, by diet...

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Cyclin D1 Overexpression and Response to Bortezomib Treatment in a Breast Cancer Model

Cited by 58 publications

References 36 publications

Consensus statement from European experts on the diagnosis, management, and treatment of multiple myeloma: from standard therapy to novel approaches

Consensus statement from European experts on the diagnosis, management, and treatment of multiple myeloma: from standard therapy to novel approaches

Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma

β‐Ionone suppresses mammary carcinogenesis, proliferative activity and induces apoptosis in the mammary gland of the Sprague‐Dawley rat

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