STAT3-mediated activation of microRNA cluster 17~92 promotes proliferation and survival of ALK-positive anaplastic large cell lymphoma.

Systemic anaplastic large cell lymphoma is a category of T-cell non-Hodgkin's lymphoma which can be further subdivided into two distinct entities (ALK(+) and ALK(-)) based on the presence or absence of ALK gene rearrangements. Among several pathways triggered by ALK signaling, constitutive activation of STAT3 is strictly required for ALK-mediated transformation and survival. Here we performed genome-wide microRNA profiling and identified 48 microRNA concordantly modulated by the inducible knock-down of ALK and STAT3.

Interplay between Ret and Fap-1 regulates CD95-mediated apoptosis in medullary thyroid cancer cells.

Emerging evidence suggests that Ret oncoproteins expressed in medullary thyroid cancer (MTC) might evade the pro-apoptotic function of the dependence receptor proto-Ret by directly impacting the apoptosis machinery. Identification of the molecular determinants of the interplay between Ret signaling and apoptosis might provide a relevant contribution to the optimization of Ret-targeted therapies. Here, we describe the cross-talk between Ret-M918T oncogenic mutant responsible for type 2B multiple endocrine syndrome (MEN2B), and components of death receptor-mediated extrinsic apoptosis pathway.

Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting.

The identification of proliferation/survival pathways constitutively activated by genetic alterations in multiple myeloma (MM), or sustained by the bone marrow (BM) microenvironment, provides novel opportunities for the development of targeted therapies. The deregulated function of protein tyrosine kinases plays a critical role in driving MM malignant phenotype. We investigated the effects of the multi-target tyrosine kinase inhibitor RPI-1 in a panel of human MM cell lines, including t(4;14) positive cell lines expressing the TK receptor FGF-R3.

Synthesis and RET protein kinase inhibitory activity of 3-arylureidobenzylidene-indolin-2-ones.

A novel series of 3-arylureidobenzylidene-indolin-2-ones was synthesized and their inhibitory activity against Ret tyrosine kinase investigated in comparison with the Ret inhibitor RPI-1 as a reference compound for this series. A few compounds were able to revert the RETC634R oncogene-transformed morphologic phenotype of NIH3T3(MEN2A) cells and showed a selective antiproliferative activity against these cells as compared to parental NIH3T3 cells or NIH3T3 cells transformed with a non-tyrosine kinase oncogene (NIH3T3(H-RAS)). Inhibition of Ret enzyme activity by effective derivatives was confirmed in a kinase assay.

Effect of paclitaxel on intracellular localization of c-Myc and P-c-Myc in prostate carcinoma cell lines.

The proto-oncogene c-myc is involved in multiple cell pathways with opposite effects on cell outcome of death or proliferation. It has been proposed that these different roles depend on the sequestration of c-Myc protein in cellular compartments and/or its phosphorylation. We speculated that subcellular localization of c-Myc protein and of its phosphorylated form (P-c-Myc) could have a role in the different response to paclitaxel (PTX) in two prostate carcinoma cell lines, PC3 and DU145, which undergo either multinucleation or c-myc-dependent apoptosis, respectively.

Inhibition of c-Met and prevention of spontaneous metastatic spreading by the 2-indolinone RPI-1.

Hepatocyte growth factor (HGF) and its tyrosine kinase receptor Met play a pivotal role in the tumor metastatic phenotype and represent attractive therapeutic targets. We investigated the biochemical and biological effects of the tyrosine kinase inhibitor RPI-1 on the human lung cancer cell lines H460 and N592, which express constitutively active Met. RPI-1-treated cells showed down-regulation of Met activation and expression, inhibition of HGF/Met-dependent downstream signaling involving AKT, signal transducers and activators of transcription 3 and paxillin, as well as a reduced expression of the proangiogenic factors vascular endothelial growth factor and basic fibroblast growth factor.

Apoptotic cell death induction and angiogenesis inhibition in large established medullary thyroid carcinoma xenografts by Ret inhibitor RPI-1.

Recent evidence indicates that the success of molecular targeted therapies may depend on the identification of drug targets which are essential for the survival of subsets of tumors. RET oncogenes that have been implicated in the development of thyroid carcinomas are emerging as potential therapeutic targets. In the present study, we investigated the efficacy and the cellular bases of antitumor activity of the indolinone Ret tyrosine kinase inhibitor RPI-1 against large established s.

Cellular effects and antitumor activity of RET inhibitor RPI-1 on MEN2A-associated medullary thyroid carcinoma.

Background: The RET proto-oncogene encodes a receptor tyrosine kinase. RET oncogenes arise through sporadic and inherited gene mutations and are involved in the etiopathogenesis of medullary thyroid carcinoma, a cancer that responds poorly to conventional chemotherapy. Medullary thyroid carcinoma is a component of multiple endocrine neoplasia type 2 or MEN2 syndromes.

RET/PTC oncoproteins: molecular targets of new drugs.

Ret oncoproteins expressed in thyroid carcinomas represent possible targets for therapeutic intervention. Oncogenic activation of the receptor tyrosine kinase encoding RET gene occurs typically by gene rearrangement in papillary thyroid carcinomas (PTC) and by missense mutation in medullary thyroid carcinomas (MTC). These genetic alterations lead to the expression of deregulated products characterized by ligand-independent activation of the intrinsic tyrosine kinase of Ret.

Cellular bases of the antitumor activity of the novel taxane IDN 5109 (BAY59-8862) on hormone-refractory prostate cancer.

Taxane-based therapies appear to have a significant efficacy in clinical trials on hormone-refractory prostate carcinoma. In the present study, we investigated the cellular response of androgen-independent prostate carcinoma cell lines to the novel taxane IDN 5109 (BAY 59-8862) and evaluated its antitumor activity. In previous preclinical studies, this new paclitaxel (PTX) analogue was characterized by high tolerability and antitumor efficacy, ability to overcome multidrug resistance, and activity by oral administration.