Mcl-1 Is a Novel Therapeutic Target for Human Sarcoma

Thallinger, Christiane; Wolschek, Markus; Maierhofer, Helmut; Skvara, Hans; Pehamberger, Hubert; Monia, Brett P.; Jansen, Burkhard; Wacheck, Volker; Selzer, Edgar

doi:10.1158/1078-0432.ccr-03-0774

Cited by 60 publications

(51 citation statements)

References 55 publications

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“…To determine whether reduced Mcl-1 expression will sensitize cells to etoposide-induced apoptosis, antisense oligonucleotides against Mcl-1 were transfected into MDA-MB-231 cells and the amount of etoposide-induced apoptosis was determined. Previously, we and other have shown that antisense oligonucleotides against Mcl-1 were specific for Mcl-1 and not other Bcl-2 family members (14,22,23). Etoposide treatment alone induced 18% apoptosis, whereas antisense, sense, and scrambled oligonucleotides against Mcl-1 failed to induce apoptosis.…”

Section: Resultsmentioning

confidence: 66%

Herceptin Sensitizes ErbB2–Overexpressing Cells to Apoptosis by Reducing Antiapoptotic Mcl-1 Expression

Henson

Gibson

2006

Clinical Cancer Research

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Purpose: Monoclonal antibodies, such as herceptin and trastuzumab, against the epidermal growth factor receptor ErbB2 (also known as HER2/neu) are an effective therapy for breast cancer patients with overexpression of ErbB2. Herceptin, in combination with standard chemotherapy, such as taxol or etoposide, gives a synergistically apoptotic response in breast tumors. Experimental Design: The mechanism underlying this synergy between chemotherapy and herceptin treatment is not well understood. Herein, we have determined that addition of herceptin, sensitized breast cancer cell lines MDA-MB-231 and MCF-7 to etoposide-or taxol-induced apoptosis.Results: This treatment resulted in reduced expression of ErbB2 and the antiapoptotic Bcl-2 family member Mcl-1 in MDA-MB-231 cells. Using antisense oligonucleotides against Mcl-1, MDA-MB-231cells were rendered sensitive to etoposide-induced apoptosis similar to herceptin, but combined treatment of antisense against Mcl-1 and herceptin failed to give a significant increase in apoptosis. In 29 human breast tumors immunostained for ErbB2 and Mcl-1, we found that when ErbB2 was overexpressed, there was a corresponding increase in Mcl-1expression. Discussion: Using murine fibroblasts that express human ErbB2, but no other ErbB family member (NE2), these cells showed resistance to both taxol-and etoposide-induced apoptosis compared with parental cells. In addition, NE2 cells preferentially express the antiapoptotic Bcl-2 family member Mcl-1compared with parental cells, and treatment with herceptin reduces Mcl-1 expression. Taken together, these results suggest that herceptin sensitizes ErbB2-overexpressing cells to apoptosis by reducing antiapoptotic Mcl-1protein levels.

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Section: Resultsmentioning

confidence: 66%

Herceptin Sensitizes ErbB2–Overexpressing Cells to Apoptosis by Reducing Antiapoptotic Mcl-1 Expression

Henson

Gibson

2006

Clinical Cancer Research

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“…Remarkably, these observations are in contrast to previous studies for solid tumors, where silencing of Mcl-1 by itself did not reveal a significantly altered phenotype. 31,38 This finding highlights the biological relevance of Mcl-1 for gastric cancer. Such a prominent role for Mcl-1 expression for cell survival has been reported so far primarily for hematological malignancies like myeloma and leukaemia.…”

Section: Discussionmentioning

confidence: 67%

“…Western blotting of lysed cells for Mcl-1 and Tubulin was performed as described previously. 31 In brief, whole cell extracts were prepared using 0.14 M NaCl, 0.2 M Triethanolamine, 0.2% Na-deoxycholate, and 0.5% Nonidet P-40, supplemented with protease inhibitors (all Sigma, St. Louis, MO, USA). Ten micrograms of total protein were separated on SDS-PAGE and blotted to PVDF membranes (Tropix, Bedford, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

Mcl-1 is a relevant molecular target for antisense oligonucleotide strategies in gastric cancer cells

Wacheck¹,

Cejka²,

Losert³

et al. 2006

Cancer Biology & Therapy

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“…Because Mcl-1 is well known as an antiapoptotic protein, it might be expected that Mcl-1 would be expressed at higher levels in patients with a worse response to radiotherapy and chemotherapy (27,41).…”

Section: Discussionmentioning

confidence: 99%

Mcl-1, Vascular Endothelial Growth Factor-R2, and 14-3-3σ Expression Might Predict Primary Response against Radiotherapy and Chemotherapy in Patients with Locally Advanced Squamous Cell Carcinomas of the Head and Neck

Erovic

Pelzmann²,

Grasl

et al. 2005

Clinical Cancer Research

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Purpose: This study was done to explore whether the expression of a selected set of proteins could predict primary response to radiotherapy or concomitant radiotherapy and chemotherapy in patients with advanced head and neck cancer. Experimental Design: Forty-three pretreatment tumor biopsies were taken during diagnostic panendoscopy and examined for Mcl-1, vascular endothelial growth factor (VEGF)-R2, CD9, and 14-3-3σ expression by immunohistochemistry. Forty-three patients underwent primary radiotherapy, of which, 29 patients received concomitant chemotherapy (low dose daily cisplatin, mitomycin C bolus). The primary end-point was locoregional tumor control 6 months after completion of radiotherapy. Mcl-1, VEGF-R2, CD9, and 14-3-3σ expression were correlated with patients' primary response to radiotherapy and chemotherapy and with established clinicopathologic variables. Results: Thirty complete and 13 partial responses were observed in our patient group. High expression levels of Mcl-1 (P = 0.021), VEGF-R2 (P = 0.032), and 14-3-3σ (P = 0.013), but not of CD9, in tumor biopsies was correlated with complete response. Overexpression of at least two of the three aforementioned proteins in pretreatment biopsies predicted—with a likelihood of 80%—whether a patient would achieve complete response to radiotherapy and chemotherapy. However, if only one of these proteins is overexpressed, there is a likelihood of 84.6% that this patient would not completely respond to therapy. Conclusion: Determining the expression levels of Mcl-1, VEGF-R2, and 14-3-3σ may be helpful in predicting the early clinical response in head and neck tumor patients receiving primary radiotherapy and chemotherapy and may further allow a pretherapeutic selection of patients.

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Mcl-1 Is a Novel Therapeutic Target for Human Sarcoma

Cited by 60 publications

References 55 publications

Herceptin Sensitizes ErbB2–Overexpressing Cells to Apoptosis by Reducing Antiapoptotic Mcl-1 Expression

Herceptin Sensitizes ErbB2–Overexpressing Cells to Apoptosis by Reducing Antiapoptotic Mcl-1 Expression

Mcl-1 is a relevant molecular target for antisense oligonucleotide strategies in gastric cancer cells

Mcl-1, Vascular Endothelial Growth Factor-R2, and 14-3-3σ Expression Might Predict Primary Response against Radiotherapy and Chemotherapy in Patients with Locally Advanced Squamous Cell Carcinomas of the Head and Neck

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