BCL-2 family proteins: Regulators of cell death involved in the pathogenesis of cancer and resistance to therapy

Reed, John C.; Miyashita, Toshiyuki; Takayama, Shinichi; Wang, Honggang; Sato, Takaaki; Krajewski, Stanisław; Aimé‐Sempé, Christine; Bodrug, Sharon; Kitada, Shinichi; Hanada, Motoi

doi:10.1002/(sici)1097-4644(19960101)60:1<23::aid-jcb5>3.0.co;2-5

Cited by 373 publications

(111 citation statements)

References 40 publications

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“…Also, Bcl-2 family members represent critical checkpoints in most apoptotic pathways acting upstream of irreversible damage to cellular constituents [17,18]. In addition, up-regulation of antiapoptotic proteins such as Bcl-2 and Bcl-X L contributes to tumorigenesis and resistance to drug treatment in certain type of cancers [33,34].…”

Section: Discussionmentioning

confidence: 99%

MEK Activation Suppresses CPT11-Induced Apoptosis in Rat Intestinal Epithelial Cells Through a COX-2-Dependent Mechanism

et al. 2007

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Resistance to chemotherapeutic agents is one of the distinct features of cancer cells. We evaluate the role of activated MEK-ERK signaling in Camptotecin/irinotecan (CPT-11)-induced cell death using constitutively activated MEK1-transfected normal rat intestinal epithelial cells (IEC-caMEK cells). A CPT-11-induced inhibitory concentration of 50% was determined by WST assay. Apoptosis was evaluated by DNA staining and fragmented DNA analysis. Protein expressions were analyzed by western blotting. We also examined the role of cyclooxygenase-2 in the cell systems. IEC-caMEK cells possessed survival advantages compared to control cells. Apoptosis was remarkably suppressed in IEC-caMEK cells. Western blot analysis revealed increased expression of Bcl-2, Bcl-xL, Mcl-1, and COX-2 and decreased expression of Bak in IEC-caMEK cells. The COX-2 selective inhibitor ameliorated the antiapoptotic nature of IEC-caMEK cells. MEK activation suppressed CPT-11-induced apoptosis in IEC-caMEK cells via a COX-2- dependent mechanism. Therefore, MEK-ERK signaling may contribute to the drug-resistant nature of cancer cells.

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Section: Discussionmentioning

confidence: 99%

MEK Activation Suppresses CPT11-Induced Apoptosis in Rat Intestinal Epithelial Cells Through a COX-2-Dependent Mechanism

et al. 2007

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“…The Bcl-2 family genes have a key role in controlling programmed cell death, or apoptosis, with some proteins in the family promoting and others (such as Bcl-2) inhibiting apoptosis [32]. A retrospective case series evaluated Bcl-2 expression (Table 1), but the authors did not find any diagnostic or predictive value for this protein [16].…”

Section: Apoptosis Regulatory Proteinsmentioning

confidence: 99%

Biomarkers predicting malignant progression of laryngeal epithelial precursor lesions: a systematic review

Rodrigo

Suárez

Takes

et al. 2011

Eur Arch Otorhinolaryngol

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Some laryngeal epithelial precursor lesions progress to invasive carcinoma and others do not. Routine light microscopic classification has limited value in predicting the evolution of these lesions. This article reviews the experience to date with the use of molecular markers for the prognostic evaluation of laryngeal epithelial precursor lesions. We conducted a thorough review of the published literature to identify those studies using biomarkers to predict malignant progression of laryngeal epithelial precursor lesions. Of the 336 studies identified in this systematic search, 15 met the inclusion criteria and form the basis of this review. Limited studies suggest that certain biomarkers are potentially reliable predictors of malignant progression including various regulators of cell adhesion and invasion (e.g. FAK, cortactin, osteopontin, and CD44v6) and proliferation-associated markers such as TGF-βRII and Kv3.4. The predictive value of these markers, however, has yet to be confirmed in large-scale prospective studies. Although the cell cycle-related proteins are the most frequently studied markers, none have been consistently reliable across multiple studies. The absence of standardization in methodologies, test interpretation, and other parameters may contribute to study inconsistencies. Various biomarkers have proved to have potential prognostic value and could be clinically relevant. The utility and prognostic power of these biomarkers should be confirmed in large, well-designed, standardized prospective studies.

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“…Additional proteins include Bax and Bad, which are found to dimerize with Bcl-2 related proteins. Overproduction of the Bcl-2 protein also prevents cell death induced by nearly all cytotoxic anticancer agents frequently contributing to treatment failures in patients with several types of cancers [20].…”

Section: Introductionmentioning

confidence: 95%

Modulation of key signal transduction molecules by a novel peptide combination effective for the treatment of gastrointestinal carcinomas

et al. 2008

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We have reported earlier a novel combination of four structurally designed synthetic neuropeptide analogs of vasoactive intestinal peptide (VIP), bombesin, substance P and somatostatin, code-named DRF 7295 which have anti-tumor efficacy for adenocarcinomas in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). The discovery, synthesis, in vitro and in vivo efficacy was reported (Jaggi et al., Invest New Drugs, 2008). Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to most sensitive to DRF7295 in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). We have further investigated and report here the modulation of cellular signaling in gastrointestinal carcinomas by DRF 7295, which may be mediating its observed anticancer activity in these cancer types. DRF 7295 inhibits the binding of specific neuropeptides initiating a cascade of cellular signaling events leading to programmed cell death. It down regulates the second messenger cAMP, epidermal growth factor (EGF) dependent proliferation and the phosphorylated MAP Kinase pERK1/2 in gastrointestinal carcinomas, thus depriving the tumour cells of critical pro-proliferative cellular signals. It triggers bcl2 and Caspase 3 dependent apoptotic cell death and induces p53 tumor suppressor protein in the treated carcinoma cells in vitro. It has significant anti-angiogenic potential as reflected in the inhibition of tube like formation in the endothelial cells and down regulation of VEGF levels. Tumour xenograft studies confirmed the in vivo efficacy of DRF 7295 for gastrointestinal carcinomas (Jaggi et al., Invest New Drugs, 2008). The Phase I clinical trials have shown DRF 7295 to be well tolerated and devoid of systemic toxicities of the conventional cytotoxics (Mukherjee et al., Phase I dose escalating study of DRF7295: a new class of peptide based drugs. "Abstract" ASCO ID:948, 2003). The drug may have a promising role in disease stabilization in colorectal and other cancers. Thus DRF 7295 is a novel targeted drug in the class of signal transduction modulators, with potential for treatment of gastrointestinal carcinomas.

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BCL-2 family proteins: Regulators of cell death involved in the pathogenesis of cancer and resistance to therapy

Cited by 373 publications

References 40 publications

MEK Activation Suppresses CPT11-Induced Apoptosis in Rat Intestinal Epithelial Cells Through a COX-2-Dependent Mechanism

MEK Activation Suppresses CPT11-Induced Apoptosis in Rat Intestinal Epithelial Cells Through a COX-2-Dependent Mechanism

Biomarkers predicting malignant progression of laryngeal epithelial precursor lesions: a systematic review

Modulation of key signal transduction molecules by a novel peptide combination effective for the treatment of gastrointestinal carcinomas

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