Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma.

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA sequencing.

Target-Based Screening against eIF4A1 Reveals the Marine Natural Product Elatol as a Novel Inhibitor of Translation Initiation with Antitumor Activity.

The DEAD-box RNA helicase eIF4A1 carries out the key enzymatic step of cap-dependent translation initiation and is a well-established target for cancer therapy, but no drug against it has entered evaluation in patients. We identified and characterized a natural compound with broad antitumor activities that emerged from the first target-based screen to identify novel eIF4A1 inhibitors. We tested potency and specificity of the marine compound elatol versus eIF4A1 ATPase activity.

Discovery of Potent 17β-Hydroxywithanolides for Castration-Resistant Prostate Cancer by High-Throughput Screening of a Natural Products Library for Androgen-Induced Gene Expression Inhibitors.

Prostate cancer (PC) is the second most prevalent cancer among men in Western societies, and those who develop metastatic castration-resistant PC (CRPC) invariably succumb to the disease. The need for effective treatments for CRPC is a pressing concern, especially due to limited durable responses with currently employed therapies. Here, we demonstrate the successful application of a high-throughput gene-expression profiling assay directly targeting genes of the androgen receptor pathway to screen a natural products library leading to the identification of 17β-hydroxywithanolides 1-5, of which physachenolide D (5) exhibited potent and selective in vitro activity against two PC cell lines, LNCaP and PC-3.

The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts.

Epidermal growth factor receptor (EGFR) inhibitors such as gefitinib show antitumor activity in a subset of non-small cell lung cancer (NSCLC) patients having mutated EGFR. Recent work shows that phosphatidylinositol-3-kinase (PI3-K) is coupled to the EGFR only in NSCLC cell lines expressing ErbB-3 and that EGFR inhibitors do not inhibit PI3-K signaling in these cells. The central role PI3-K plays in cell survival suggests that a PI3-K inhibitor offers a strategy to increase the antitumor activity of EGFR inhibitors in resistant NSCL tumors that do not express ErbB-3.

Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling.

We have developed biologically stable semisynthetic viridins as inhibitors of phosphoinositide (PtdIns)-3-kinases. The most active compound was PX-866 (acetic acid (1S,4E,10R,11R,13S,14R)-[4-diallylaminomethylene-6-hydroxy-1-methoxymethyl-10,13-dimethyl-3,7,17-trioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopenta[a]phenanthren-11-yl ester), which inhibited purified PtdIns-3-kinase with an IC50 of 0.1 nmol/L and PtdIns-3-kinase signaling measured by phospho-Ser473-Akt levels in HT-29 colon cancer cells with an IC50 of 20 nmol/L.

Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha.

The hypoxia-inducible factor-1 (HIF-1) transcription factor is an important regulator of tumor response to hypoxia that include increased angiogenesis, glycolytic metabolism, and resistance to apoptosis. HIF-1 activity is regulated by the availability of the HIF-1alpha subunit, the levels of which increase under hypoxic conditions. PX-478 (S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) is an inhibitor of constitutive and hypoxia-induced HIF-1alpha levels and thus HIF-1 activity.

Hormone-refractory breast cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors.

Purpose: The antiestrogen tamoxifen (Tam) has been used as therapy against estrogen receptor (ER)-positive breast cancer for decades. Most tumors respond initially, but resistance frequently develops. The ER exists in a multiprotein complex containing the molecular chaperone heat shock protein (Hsp) 90, which is known to regulate the stability and activity of this receptor.

Destabilization of steroid receptors by heat shock protein 90-binding drugs: a ligand-independent approach to hormonal therapy of breast cancer.

Steroid hormone receptors have become an important target in the management of breast cancers. Despite a good initial response rate, however, most tumors become refractory to current hormonal therapies within a year of starting treatment. To address this problem, we evaluated the effects of agents that bind the molecular chaperone heat shock protein 90 (Hsp90) on estrogen receptor function in breast cancer.

Induction of a heat shock factor 1-dependent stress response alters the cytotoxic activity of hsp90-binding agents.

In addition to its classic role in the cellular stress response, heat shock protein 90 (Hsp90) plays a critical but less well appreciated role in regulating signal transduction pathways that control cell growth and survival under basal, nonstress conditions. Over the past 5 years, the antitumor antibiotics geldanamycin and radicicol have become recognized as selective Hsp90-binding agents (HBA) with a novel ability to alter the activity of many of the receptors, kinases, and transcription factors involved in these cancer-associated pathways. As a consequence of their interaction with Hsp90, however, these agents also induce a marked cellular heat shock response.

Early increases in breast tumor xenograft water mobility in response to paclitaxel therapy detected by non-invasive diffusion magnetic resonance imaging.

An important goal in cancer chemotherapy is to sensitively and quantitatively monitor the response of individual patients' tumors to successful, or unsuccessful, therapy so that regimens can be altered iteratively. Currently, tumor response is monitored by frank changes in tumor morphology, yet these markers take long to manifest and are not quantitative. Recent studies suggest that the apparent diffusion coefficient of water (ADCw), measured noninvasively with magnetic resonance imaging, is sensitively and reliably increased in response to successful CTx.

Wortmannin inhibits the growth of mammary tumors despite the existence of a novel wortmannin-insensitive phosphatidylinositol-3-kinase.

Purpose: Phosphatidylinositol (PtdIns) 3-kinase is an important mediator of many cellular functions. The study of PtdIns 3-kinase has been facilitated by the existence of the potent irreversible inhibitor of p110 PtdIns 3-kinase, wortmannin. The purpose of the study was to investigate the relationship between the cell growth inhibitory activity and antitumor activity of wortmannin and inhibition of PtdIns 3-kinase.

Enhancement of chemotherapy by manipulation of tumour pH.

The extracellular (interstitial) pH (pHe) of solid tumours is significantly more acidic compared to normal tissues. In-vitro, low pH reduces the uptake of weakly basic chemotherapeutic drugs and, hence, reduces their cytotoxicity. This phenomenon has been postulated to contribute to a 'physiological' resistance to weakly basic drugs in vivo.

Diaryl chalcogenides as selective inhibitors of thioredoxin reductase and potential antitumor agents.

Thioredoxin reductase is a selenocysteine containing flavoenzyme that catalyzes the NADPH dependent reduction of the redox protein thioredoxin. Thioredoxin is over-expressed by a number of human tumors. Experimental studies have shown that thioredoxin is responsible for the growth and transformed phenotype of some human cancer cells.

Amifostine protects normal tissues from paclitaxel toxicity while cytotoxicity against tumour cells is maintained.

The objectives of this study were to evaluate the protective effects of amifostine against paclitaxel-induced toxicity to normal and malignant human tissues. Haematopoietic progenitor colony assays were used to establish the number of CFU-GEMM and BFU-E colonies after incubation with WR-1065 alone, Amifostine alone, paclitaxel (2.5 or 5 microM) +/- WR-1065 or amifostine.

Human tumor models in the severe combined immune deficient (scid) mouse.

Purpose: To test a number of established human tumor cell lines and early passage breast cancer (UACC2150) and melanoma cells (UACC1273) for growth in the scid mouse and the tumors' response to conventional chemotherapeutic drugs.

Methods: Established melanoma (A375, C81-61), colon (SW480), lung (A549), lymphomoblastoid leukemia (LCL-B), promyelocytic leukemia (HL60), prostate (PC-3, DU145), and breast (MCF7) cell lines were injected at subcutaneous (s.c.

Transfection with human thioredoxin increases cell proliferation and a dominant-negative mutant thioredoxin reverses the transformed phenotype of human breast cancer cells.

Thioredoxin, a redox protein with growth factor activity that modulates the activity of several proteins important for cell growth, has been reported to be overexpressed in a number of human primary cancers. In the present study, the effects of stably transfecting mouse NIH 3T3 cells and MCF-7 human breast cancer cells with cDNA for wild-type human thioredoxin or a redox-inactive mutant thioredoxin, Cys32-->Ser32/Cys35-->Ser35 (C32S/C35S), on cell proliferation and transformed phenotype have been investigated. NIH 3T3 cells transfected with thioredoxin achieved increased saturation densities compared with vector alone-transfected cells, but were not transformed as assessed by tumor formation in immunodeficient mice.