Paclitaxel Directly Binds to Bcl-2 and Functionally Mimics Activity of Nur77

Ferlini, Cristiano; Cicchillitti, Lucia; Raspaglio, Giuseppina; Bartollino, Silvia; Cimitan, Samanta; Bertucci, Carlo; Mozzetti, Simona; Gallo, Daniela; Persico, Marco; Fattorusso, Caterina; Campiani, Giuseppe; Scambia, Giovanni

doi:10.1158/0008-5472.can-09-0540

Cited by 135 publications

(109 citation statements)

References 34 publications

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“…This however was not surprising since paclitaxel, targets cancer cells by driving them to apoptosis. 29 When administration of mAb 4C5 was combined with paclitaxel, regression of the tumors was statistically very significant, as estimated by weight measurements and Ki-67 immunolabeling which was almost absent. Additionally, in these tumors vast areas of cell necrosis were observed.…”

Section: Discussionmentioning

confidence: 95%

“…Additionally we investigate the effect of mAb 4C5 in in vivo primary growth of tumors derived from MDA-MB-231 cells and their corresponding BCSC. Finally we explore the therapeutic capacity of mAb4C5 alone and in combination with paclitaxel, an established anti-cancer agent, 28,29 on the progression of established primary tumors generated by MDA-MB-231-derived BCSC.…”

Section: Introductionmentioning

confidence: 99%

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Targeting highly expressed extracellular HSP90 in breast cancer stem cells inhibits tumor growthin vitroandin vivo

Stivarou

Stellas

Vartzi

et al. 2016

Cancer Biology & Therapy

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Breast cancer stem cells (BCSC) have been identified in breast carcinoma as CD44 C /CD24 ¡/low cells, which display tumorigenic activity and have the ability to self-renew, differentiate and metastasize. Previous studies showed that extracellular HSP90 (eHSP90) participates in the invasion and metastatic processes of various cancers including breast cancer. Here, we show for the first time that eHSP90 is over-expressed in mammosphere cultures that are derived from the MDA-MB-231, MDA-MB-453 and MCF-7 breast cancer cell lines. These mammospheres are highly enriched in cells of the CD44 C /CD24 ¡/low BCSC phenotype and additionally show high expression of the BCSC markers CD49f and Sox2. Thus our results indicate that eHSP90 represents a potential novel BCSC marker. Moreover, we present evidence that eHSP90 is functionally involved in BCSC activity in vitro and in vivo. Selective neutralization of eHSP90, using the monoclonal antibody mAb 4C5, has the capacity to inhibit stem cell activity in vitro because the formation of mammosphere-derived colonies is dramatically reduced in its presence. In vivo, the treatment of mice with mAb4C5 using a prophylactic protocol, significantly inhibited the primary growth of MDA-MB-231 and mammosphere-derived tumors. More importantly, administration of this antibody in a therapeutic protocol caused a statistically significant regression of established tumors derived from MDA-MB-231 originating mammospheres. Tumor regression was even greater when mAb 4C5 was administered in combination with paclitaxel. Overall, our findings implicate eHSP90 as a potential novel BCSC biomarker. Moreover they show that eHSP90 participates in BCSC-derived primary tumor growth. Finally, we provide additional support for the possible therapeutic value of mAb4C5 in the treatment of breast cancer.Abbreviations: ALDH1, aldehyde dehydrogenase 1; BCSC, breast cancer stem cells; eHSP90, extracellular heat shock protein 90; ER, estrogen receptor; EGF, epidermal growth factor; FGF, fibroblast growth factor; MMP-2, matrix metalloproteinase 2

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Targeting highly expressed extracellular HSP90 in breast cancer stem cells inhibits tumor growthin vitroandin vivo

Stivarou

Stellas

Vartzi

et al. 2016

Cancer Biology & Therapy

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“…It also binds directly to Bcl-2, a prosurvival protein, changing its function and initiating apoptosis 456 .…”

Section: Paclitaxelmentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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“…Procedures and facilities was administered at the MTD, and according to a conventional schedule treatment able to achieve a 60% cure rate in the sensitive A2780 ovarian cancer model [24]. IP paclitaxel was administered at its MTD determined in preliminary studies (unpublished results), with the same regimen as ONCOFID-P.…”

Section: Animals and Treatmentsmentioning

confidence: 99%