The Trk tyrosine kinase inhibitor K252a regulates growth of lung adenocarcinomas

Pérez-Piñera, Pablo; Hernández, Tatiana; García‐Suárez, Olivia; Carlos, Félix de; Germanà, Antonino; Soto, Miguel; Astudillo, Aurora; Vega, J.A.

doi:10.1007/s11010-006-9267-7

Cited by 50 publications

(41 citation statements)

References 27 publications

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“…Increased BDNF and TrkB expressions have recently been found in several human tumors (13)(14)(15). BDNF/TrkB promote cancer cell survival and resistance to chemotherapy, while small-molecule inhibitors of Trk, such as K252α, inhibit cell growth and induce apoptotic death in cancer cells (16)(17)(18)(19). TrkB expression has been described in ovarian and cervical cancers (20,21), while being associated with a shorter survival and the promotion of metastasis in ovarian cancer patients (20 in cell proliferation, migration and suppression of anoikis (22,23).…”

Section: Introductionmentioning

confidence: 99%

Influence of GRPR and BDNF/TrkB signaling on the viability of breast and gynecologic cancer cells

Cornélio

Farias

Prusch

et al. 2012

Molecular and Clinical Oncology

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Abstract. Neuropeptide and neurotrophin receptors are increasingly important molecular targets in cancer. Scientific findings indicate that compounds blocking gastrin-releasing peptide receptors (GRPR) or tropomyosin receptor kinase (Trk) receptors are likely to have antiproliferative activities against cancer cells. The present study aimed to demonstrate that, in contrast to previous findings, GRPR activation reduces, whereas its blockade increases the viability of breast, ovarian and cervical cancer cell lines. However, consistent with previous studies, Trk inhibition was demonstrated to reduce the viability of these cells. MCF-7 (breast), OVCAR-3 (ovarian) and HeLa (cervical) human cancer cell lines were treated with GRP, the GRPR antagonists RC-3095 and RC-3940-II, brain-derived neurotrophic factor (BDNF) and the Trk antagonist K252α. Cell viability was measured by the MTT assay. Expression of GRPR and BDNF was confirmed with reverse transcription-polymerase chain reaction (RT-PCR). GRP reduced, whereas RC-3940-II enhanced the viability of the three cell lines. Treatment with K252α inhibited the viability of the cell lines, while BDNF increased the viability of OVCAR-3 cells. The results supported the hypothesis that GRPR and BDNF/TrkB signaling regulates cancer cell viability. Most importantly, these findings are the first to demonstrate that GRPR blockade can stimulate, rather than inhibits the viability of breast and gynecologic cancer cell lines.

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Section: Introductionmentioning

confidence: 99%

Influence of GRPR and BDNF/TrkB signaling on the viability of breast and gynecologic cancer cells

Cornélio

Farias

Prusch

et al. 2012

Molecular and Clinical Oncology

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“…In addition, NTs play a role in the modulation of certain human malignancies (29,30), such as myeloma (31), fibrosarcoma (32), hepatocellular (33) and pancreatic (34) carcinoma as well as lung cancer (35,36). More importantly, there is in vitro evidence that compounds blocking NT signaling, such as k252a, are able to block lung cancer cell progression (37). Yet, to date, the role of NTs in malignant pleural effusion (38) and in mesothelioma (39) has been poorly investigated.…”

Section: Introductionmentioning

confidence: 99%

Diagnostic value of neurotrophin expression in malignant pleural effusions

Duysinx

Paulus

Heinen

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Neurotrophins (NTs) modulate the growth of human malignancies, including lung cancers. Our prospective study evaluated the accuracy of pleural NTs [nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin 3 (nT3) and 4 (nT4)] levels for differentiating benign from malignant pleural exudates. Levels of NTs were measured by ELISA in 170 patients with non-neutrophilic (<50%) exudative benign or malignant pleurisies diagnosed by pleuroscopy. Fifty-nine benign (9 infections and 50 inflammatory diseases) and 111 malignant (50 extrathoracic tumors, 51 lung cancers and 10 mesotheliomas) pleural exudates were diagnosed by thoracoscopy. Levels of BDNF were significantly higher in malignant than in benign effusions [17 pg/ml (0-367) vs. 8 pg/ml (0-51), p<0.05]. ROC analysis showed an area under the curve of 0.609 (p=0.012; best threshold 44 pg/ml). Pleural BDNF levels were significantly higher in pleural metastasis of pulmonary tumors and in mesothelioma than in pleural benign effusions. Finally, a higher proportion of pleural nT3 was detected in squamous cell lung carcinoma in comparison to that in nonsquamous cell lung carcinoma (72.7 vs. 10%, p<0.0001). NTs and particularly BDNF may play a role in the pathogenesis of malignant pleural effusions.

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“…For reprint orders, please contact reprints@expert-reviews.com lung adenocarcinoma cells with BDNF stimulated the prosurvival Akt pathway, while the Trk inhibitor K252a inhibited cell growth and induced apoptotic cell death [8]. TrkB mutations have been identified in non-small-cell lung cancer; however, these mutations did not result in enhanced cell transformation and migration [9].…”

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confidence: 99%