benzofurans and Neoplasm-Metastasis

Direct randomized comparisons of regorafenib, TAS-102, and fruquintinib for treating metastatic colorectal cancer (mCRC) are lacking. Here, we evaluated the efficacy and safety of three agents by a systematic review and a network meta-analysis.. We included phase III randomized controlled trials in the PubMed, Embase, and Scopus Cochrane databases and ClinicalTrials.gov registry from initiation until January 2019. Data from randomized controlled trials including overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were extracted. Direct meta-analysis and indirect meta-analysis using network meta-analysis were assessed.. Five trials comprising a total of 2586 patients were included. For efficacy analysis of OS, no statistically significant differences were observed between regorafenib and TAS-102 (HR 0.945, 95% CI [0.677, 1.320], P = 0.753), regorafenib and fruquintinib (HR 1.056, 95% CI [0.690, 1.621], P = 0.814), or TAS-102 and fruquintinib (HR 1.117, 95% CI [0.740, 1.685], P = 0.610). However, fruquintinib was superior in PFS compared with TAS-102 (HR 1.756, 95% CI [1.079, 2.857], P = 0.023). Regorafenib and TAS-102 appeared to have a similar effect on PFS (HR 0.907, 95% CI [0.611, 1.346], P = 0.641), as did regorafenib and fruquintinib (HR 1.592, 95% CI [0.968, 2.618], P = 0.067). None of the three agents were better in terms of all grade AEs or any grade of 3-5 AEs. However, subgroup analysis of AEs exhibited different toxicity profiles between the three drugs.. Indirect comparison suggested that the three agents had similar OS but that fruquintinib was superior in terms of PFS compared with that of TAS-102. These three agents had different toxicity profiles.

Topics: Antineoplastic Agents; Benzofurans; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Disease Progression; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Network Meta-Analysis; Phenylurea Compounds; Progression-Free Survival; Pyridines; Pyrrolidines; Quinazolines; Randomized Controlled Trials as Topic; Thymine; Time Factors; Trifluridine; Uracil

The optimal treatment in the third-line and later-line setting for metastatic colorectal cancer (mCRC) has not been established. As reported, regorafenib and fruquintinib have shown to be superior to placebo in mCRC. However, no direct clinical comparison of regorafenib and fruquintinib has been conducted; we performed a systematic review and network meta-analysis to compare the efficacy and safety of regorafenib and fruquintinib.. PubMed, Embase, and the Cochrane Library were systematically searched and randomized-controlled trials (RCTs) assessing the effect and safety of regorafenib or fruquintinib versus placebo for patients with mCRC were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. After that, we performed pairwise direct meta-analyses (regorafenib vs. placebo and fruquintinib vs. placebo) and indirect comparison (regorafenib vs. fruquintinib) using network meta-analyses methods.. Three RCTs involving 1380 patients were included in the meta-analysis. In the direct meta-analysis, regorafenib and fruquintinib both showed survival benefits when compared with placebo. For the indirect comparison, fruquintinib shows no significant difference in OS compared to regorafenib (HR 0.97; 95% CI 0.64-1.46). Regarding PFS, there was a tendency that fruquintinib was superior to regorafenib (HR 0.65; 95% CI 0.39-1.08); however, there was no statistic difference. For the safety analysis, in indirect comparison, fruquintinib showed significant difference in all-grade toxicity compared to regorafenib (OR 0.73; 95% CI 0.65-0.82), especially in subgroup of proteinuria (OR 0.31; 95% CI 0.11-0.86). For the grade 3-5 toxicity, fruquintinib showed no significant difference when compared with regorafenib (OR 0.92; 95% CI 0.64-1.32).. Based on efficacy and safety, there was a tendency that fruquintinib was superior to regorafenib, as a whole, regorafenib and fruquintinib demonstrated similar clinical benefit for patients with refractory mCRC. It seems that fruquintinib has less toxic in all-grade toxicity when compared with regorafenib.

Topics: Benzofurans; Colorectal Neoplasms; Disease-Free Survival; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Network Meta-Analysis; Phenylurea Compounds; Pyridines; Quinazolines; Treatment Outcome

This is a phase I/II trial to assess the efficacy and safety of napabucasin plus pembrolizumab for metastatic colorectal cancer (mCRC).. Phase I was conducted to determine the recommended phase 2 dose (RP2D) in a dose escalation design of napabucasin (240 to 480 mg twice daily) with 200 mg pembrolizumab every 3 weeks. Phase II included cohort A (. A total of 55 patients were enrolled in this study. In phase I, no patients experienced dose-limiting toxicities, and napabucasin 480 mg was determined as RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. In cohort B, the irORR was 0%, 5.3%, and 42.9% in CPS < 1, 1≤ CPS <10, and CPS ≥ 10, respectively. Patients with objective response tended to have higher tumor mutation burden than those without. Of evaluable 18 patients for CMS classification in cohort B, the irORR was 33.3%, 0%, 33.3%, and 33.3% in CMS1, CMS2, CMS3, and CMS4, respectively. The common grade 3 or higher treatment-related adverse events included fever (10.0%) in cohort A and decreased appetite (7.5%) and diarrhea (5.0%) in cohort B.. Napabucasin with pembrolizumab showed antitumor activity with acceptable toxicities for patients with MSS mCRC as well as MSI-H mCRC, although it did not meet the primary end point. The impact of related biomarkers on the efficacy warrants further investigations in the additional cohort.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Benzofurans; Colorectal Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Microsatellite Instability; Middle Aged; Naphthoquinones; Neoplasm Metastasis

Napabucasin is a first-in-class cancer stemness inhibitor that targets STAT3, which is a poor prognostic factor in colorectal cancer. This study aimed to test napabucasin in advanced colorectal cancer.. This study was a double-blind randomised phase 3 trial done at 68 centres in Canada, Australia, New Zealand, and Japan. Patients with advanced colorectal cancer with a good Eastern Cooperative Oncology Group (ECOG) performance status (0-1) for whom all available standard therapies had failed were eligible for the study. Patients were randomly assigned (1:1) to receive placebo or napabucasin through a web-based system with a permuted block method, after stratification by ECOG performance status, KRAS status, previous VEGF inhibitor treatment, and time from diagnosis of metastatic disease. Napabucasin 480 mg or matching placebo was taken orally every 12 h. All patients received best supportive care. The primary endpoint was overall survival assessed in an intention-to-treat analysis. This is the final analysis of this trial, which is registered at ClinicalTrials.gov, number NCT01830621.. Accrual began on April 15, 2013, and was stopped for futility on May 23, 2014, at which point 282 patients had undergone randomisation (138 assigned to the napabucasin group and 144 to the placebo group). Overall survival did not differ significantly between groups: median overall survival was 4·4 months (95% CI 3·7-4·9) in the napabucasin group and 4·8 months (4·0-5·3) in the placebo group (adjusted hazard ratio [HR] 1·13, 95% CI 0·88-1·46, p=0·34). The safety population included 136 patients in the napabucasin group and 144 patients in the placebo group. More patients who received napabucasin had any grade of treatment-related diarrhoea (108 [79%] of 136 patients), nausea (69 [51%]), and anorexia (52 [38%]) than did patients who received placebo (28 [19%] of 144 patients, 35 [24%], and 23 [16%], respectively). The most common severe (grade 3 or worse) treatment-related adverse events were abdominal pain (five [4%] patients receiving napabucasin vs five [3%] receiving placebo), diarrhoea (21 [15%] vs one [1%]), fatigue (14 [10%] vs eight [6%]), and dehydration (six [4%] vs one [1%]). 251 (89%) patients had data on pSTAT3 expression, of whom 55 (22%) had pSTAT3-positive tumours (29 in the napabucasin group, 26 in the placebo group). In a prespecified biomarker analysis of pSTAT3-positive patients, overall survival was longer in the napabucasin group than in the placebo group (median 5·1 months [95% CI 4·0-7·5] vs 3·0 months [1·7-4·1]; HR 0·41, 0·23-0·73, p=0·0025).. Although there was no difference in overall survival between groups in the overall unselected population, STAT3 might be an important target for the treatment of colorectal cancer with elevated pSTAT3 expression. Nevertheless, these results require validation.. Canadian Cancer Society Research Institute and Boston Biomedical.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzofurans; Biomarkers, Tumor; Colorectal Neoplasms; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Naphthoquinones; Neoplasm Metastasis; Prospective Studies; STAT3 Transcription Factor; Survival Analysis; Time-to-Treatment

Adozelesin is the first of a class of DNA-sequence-selective alkylating agents, the cyclopropa(c)pyrrolo(3,2-e)indol-4(5H)-ones (CPls), that have been shown to have of potent inhibitory properties of DNA synthesis. Based on preliminary data from phase I studies showing clinical activity in patients with breast cancer, we initiated a multicenter phase II study in untreated metastatic breast carcinoma. Adozelesin was administered at a starting dose of 150 microg/m2 as a single 10 min infusion per course, repeated every 4 weeks, for up to 1 year of treatment. It was planned that at least 25 patients should be accrued but the trial was stopped early because of slow accrual and lack of efficacy as demonstrated by the infrequency of objective responses. Seventeen patients were enrolled in this study, only 14 were evaluable, the following responses were observed: one partial response (7%), three stable diseases (22%) and 10 progressive diseases (71%). Myelosuppression was the most frequent adverse event; one patient died of pulmonary complications. We conclude that adozelesin has marginal efficacy in the treatment of metastatic breast cancer at the dosage and schedule used in this study.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Benzofurans; Breast Neoplasms; Cyclohexanecarboxylic Acids; Cyclohexenes; Duocarmycins; Female; Humans; Indoles; Infusions, Intravenous; Middle Aged; Neoplasm Metastasis

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a repair enzyme for 3'-end DNA lesions, predominantly stalled DNA-topoisomerase 1 (Top1) cleavage complexes. Tdp1 is a promising target for anticancer therapy based on DNA damage caused by Top1 poisoning. Earlier, we have reported about usnic acid enamine derivatives that are Tdp1 inhibitors sensitizing tumor cells to the action of Top1 poison (Zakharenko in J Nat Prod 79:2961-2967, 2016). In the present work, we showed a sensitizing effect of an enamine derivative of usnic acid (when administered intragastrically) on Lewis lung carcinoma in mice in combination with topotecan (TPT, Top1 poison used in the clinic). In the presence of the usnic acid derivative, both the volume of the primary tumor and the number of metastases significantly diminished. The absence of acute toxicity of this compound was demonstrated, as was the importance of the method of its administration for the manifestation of the sensitizing properties.

Topics: Animals; Benzofurans; Carcinoma, Lewis Lung; Female; Male; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasm Transplantation; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Topotecan

To evaluate the cost-effectiveness of addition of fruquintinib to best supportive care (BSC) in third-line treatment for patients with metastatic colorectal cancer (CRC).. To conduct the cost-effectiveness analysis, a Markov model was established to simulate the course of metastatic CRC. Three health states-progression-free survival (PFS), progressive disease (PD), and death-were included. Clinical data were derived from the FRESCO trial and health utility values were extracted from previous literature. The primary outcome of the study was incremental cost-effectiveness ratio (ICER) in US dollars per quality-adjusted life-years (QALYs) from a Chinese societal perspective. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to test the robustness of the study.. Addition of fruquintinib to BSC gained 0.54 QALY at a cost of $15,404.57 while the BSC group gained 0.38 QALY at a cost of $9603.94. ICER of fruquintinib versus BSC was $36,253.94/QALY. In the 1-way sensitivity analyses, utility for PD in both groups, utility for PFS in both groups, and cost of fruquintinib significantly influenced the results of the analysis. At the willingness-to-pay threshold of $28,988.40/QALY, probabilities of addition of fruquintinib to BSC or BSC alone as the cost-effective option were 0% and 100%, indicating addition of fruquintinib is not a dominant option compared with BSC.. Addition of fruquintinib to BSC is not a cost-effective regimen in the third-line setting for patients with metastatic CRC from the Chinese societal perspective.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Colorectal Neoplasms; Cost-Benefit Analysis; Female; Humans; Male; Markov Chains; Neoplasm Metastasis; Progression-Free Survival; Quality-Adjusted Life Years; Quinazolines

In this study, we analyze the cost-effectiveness of fruquintinib as third-line treatment for patients with metastatic colorectal cancer in China, especially after a recent price drop suggested by the National Healthcare Security Administration.. A Markov model was developed to investigate the cost-effectiveness of fruquintinib compared to placebo among patients with metastatic colorectal cancer. Effectiveness was measured in quality-adjusted life years (QALY). The Chinese healthcare payer's perspective was considered with a lifetime horizon, including direct medical cost (2019 US dollars [USD]). A willing-to-pay threshold was set at USD 27,130/QALY, which is three times the gross domestic product (GDP) per capita. We examined the robustness of the model in one-way and probabilistic sensitivity analysis.. Fruquintinib was associated with better health outcomes than placebo (0.640 vs 0.478 QALYs) with a higher cost (USD 20750.9 vs USD 12042.2), resulting in an incremental cost-effectiveness ratio (ICER) of USD 53508.7 per QALY. This ICER is 25% lower than the one calculated before the price drop (USD 70952.6 per QALY).. After the price negotiation, the drug becomes cheaper and the ICER is lower, but the drug is still not cost effective under the standard of 3 times GDP willing-to-pay threshold. For patients with metastatic colorectal cancer in China, fruquintinib is not a cost-effective option under the current circumstances in China.

Topics: Benzofurans; China; Colorectal Neoplasms; Cost-Benefit Analysis; Humans; Neoplasm Metastasis; Quinazolines

Fruquintinib is a potent, highly selective and orally active inhibitor of VEGFR1, 2, 3 tyrosine kinases. It inhibits VEGF-induced VEGFR2 phosphorylation, endothelial cell proliferation and tubule formation. Currently, it has been approved for the treatment of metastatic colorectal cancer in patients who have failed at least two prior systemic antineoplastic therapies in China. However, it is not approved outside China, and there is another similar small molecular VEGFR multitarget drug approved in China, USA, Europe, etc. Here, we summarize the mechanism characteristics and clinical development of fruquintinib supporting its use in the treatment of metastastic colorectal cancer as well as explorations in other tumor types.

Topics: Angiogenesis Inhibitors; Benzofurans; Cell Proliferation; China; Clinical Trials as Topic; Colorectal Neoplasms; Europe; Humans; Neoplasm Metastasis; Neovascularization, Pathologic; Phosphorylation; Quinazolines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Cancer metastasis causes approximately 90% of all cancer-related death and independent of the advancement of cancer therapy, a majority of late stage patients suffers from metastatic cancer. Metastasis implies cancer cell migration and invasion throughout the body. Migration requires the formation of pseudopodia in the direction of movement, but a detailed understanding of this process and accordingly strategies of prevention remain elusive. Here, we use quantitative proteomic profiling of human cancer pseudopodia to examine this mechanisms essential to metastasis formation, and identify potential candidates for pharmacological interference with the process. We demonstrate that Prohibitins (PHBs) are significantly enriched in the pseudopodia fraction derived from cancer cells, and knockdown of PHBs, as well as their chemical inhibition through Rocaglamide (Roc-A), efficiently reduces cancer cell migration.

Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Cell Movement; Gene Knockdown Techniques; Humans; Neoplasm Metastasis; Prohibitins; Proteomics; Pseudopodia; Repressor Proteins

Osteosarcoma is the most common bone cancer. Despite advances, molecular mechanisms associated with osteosarcoma have not been fully understood. Hence, an effective treatment for osteosarcoma has yet to be developed. Even though signal transducer and activator of transcription3 (STAT3) has been implicated, its role in pathogenesis of osteosarcoma is not fully determined. In this study, we investigated the antitumor effect of napabucasin (NP) (BBI608), an inhibitor of STAT3 on osteosarcoma in vitro and in vivo and studied the underlying molecular mechanism.. Cell viability, colony formation, apoptosis, tumor growth and metastasis assays were performed to examine the effect of NP on osteosarcoma in vitro and in vivo. Real-time RT-PCR, western analysis, immunofluorescence and reporter assays were used to monitor the expression and activity of proteins and underlying molecular pathways. Protein synthesis, co-immunoprecipitation and CAP binding assays were carried out to understand NP-mediated mechanism of actions in osteosarcoma cells.. Our results show that NP treatment decreases cell viability and induces apoptosis in several osteosarcoma cell lines. NP treatment suppresses both expression and phosphorylation of STAT3 in addition to blocking STAT3-mediated transcription and downstream target proteins in osteosarcoma cells. Furthermore, NP inhibits protein synthesis through regulation of the eukaryotic initiation factor 4E (eIF4E) and eIF4E-binding protein 1 (4E-BP1). NP also inhibits the progression of osteosarcoma tumors and metastasis in vivo in an orthotopic tibial model of osteosarcoma.. Taken together, our investigation reveals that NP acts through a novel mechanism and inhibits osteosarcoma growth and metastasis, and could be investigated clinically for treating osteosarcoma patients alone or in combination with other drugs.

Topics: Animals; Apoptosis; Benzofurans; Bone Neoplasms; Cell Line, Tumor; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Naphthoquinones; Neoplasm Metastasis; Osteosarcoma; Protein Synthesis Inhibitors; Random Allocation; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Lichens are symbiotic organisms that produce various unique chemicals that can be used for pharmaceutical purposes. With the aim of screening new anti-cancer agents that inhibit cancer cell motility, we tested the inhibitory activity of seven lichen species collected from the Romanian Carpathian Mountains against migration and invasion of human lung cancer cells and further investigated the molecular mechanisms underlying their anti-metastatic activity. Among them, Alectoria samentosa, Flavocetraria nivalis, Alectoria ochroleuca, and Usnea florida showed significant inhibitory activity against motility of human lung cancer cells. HPLC results showed that usnic acid is the main compound in these lichens, and (+)-usnic acid showed similar inhibitory activity that crude extract have. Mechanistically, β-catenin-mediated TOPFLASH activity and KITENIN-mediated AP-1 activity were decreased by (+)-usnic acid treatment in a dose-dependent manner. The quantitative real-time PCR data showed that (+)-usnic acid decreased the mRNA level of CD44, Cyclin D1 and c-myc, which are the downstream target genes of both β-catenin/LEF and c-jun/AP-1. Also, Rac1 and RhoA activities were decreased by treatment with (+)-usnic acid. Interestingly, higher inhibitory activity for cell invasion was observed when cells were treated with (+)-usnic acid and cetuximab. These results implied that (+)-usnic acid might have potential activity in inhibition of cancer cell metastasis, and (+)-usnic acid could be used for anti-cancer therapy with a distinct mechanisms of action.

Topics: Antineoplastic Agents; Benzofurans; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Chromatography, High Pressure Liquid; Chromatography, Liquid; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HEK293 Cells; Humans; Inhibitory Concentration 50; Lichens; Lung Neoplasms; Mass Spectrometry; Neoplasm Invasiveness; Neoplasm Metastasis; Real-Time Polymerase Chain Reaction; Romania

Experimental studies in preclinical mouse models of breast cancer have shown that chronic restraint stress can enhance disease progression by increasing catecholamine levels and subsequent signaling of β-adrenergic receptors. Catecholamines also signal α-adrenergic receptors, and greater α-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of α-adrenergic receptors can result in elevated catecholamine levels, which may increase β-adrenergic signaling, because pre-synaptic α2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of α-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective α-adrenergic blockade by phentolamine significantly inhibited those effects. However, under non-stress conditions, phentolamine increased primary tumor size and distant metastasis. Sympatho-neural gene expression for catecholamine biosynthesis enzymes was elevated by phentolamine under non-stress conditions, and the non-selective β-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective α2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective α1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that α2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of β-adrenergic signaling on tumor progression-relevant biology.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Antagonists; Animals; Benzofurans; Cell Proliferation; Disease Progression; Female; Imidazoles; Mammary Neoplasms, Experimental; Mice; Neoplasm Metastasis; Prazosin; Restraint, Physical; Signal Transduction; Stress, Physiological; Stress, Psychological

Partial or even complete cancer regression can be achieved in some patients with current cancer treatments. However, such initial responses are almost always followed by relapse, with the recurrent cancer being resistant to further treatments. The discovery of therapeutic approaches that counteract relapse is, therefore, essential for advancing cancer medicine. Cancer cells are extremely heterogeneous, even in each individual patient, in terms of their malignant potential, drug sensitivity, and their potential to metastasize and cause relapse. Indeed, hypermalignant cancer cells, termed cancer stem cells or stemness-high cancer cells, that are highly tumorigenic and metastatic have been isolated from cancer patients with a variety of tumor types. Moreover, such stemness-high cancer cells are resistant to conventional chemotherapy and radiation. Here we show that BBI608, a small molecule identified by its ability to inhibit gene transcription driven by Stat3 and cancer stemness properties, can inhibit stemness gene expression and block spherogenesis of or kill stemness-high cancer cells isolated from a variety of cancer types. Moreover, cancer relapse and metastasis were effectively blocked by BBI608 in mice. These data demonstrate targeting cancer stemness as a novel approach to develop the next generation of cancer therapeutics to suppress cancer relapse and metastasis.

Topics: Animals; Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Dose-Response Relationship, Drug; Heterografts; Inhibitory Concentration 50; Mice; Naphthoquinones; Neoplasm Metastasis; Neoplastic Stem Cells; Secondary Prevention

Activation of the translation initiation factor 4E (eIF4E) promotes malignant transformation and metastasis. Signaling through the AKT-mTOR pathway activates eIF4E by phosphorylating the inhibitory 4E binding proteins (4E-BP). This liberates eIF4E and allows binding to eIF4G. eIF4E can then be phosphorylated at serine 209 by the MAPK-interacting kinases (Mnk), which also interact with eIF4G. Although dispensable for normal development, Mnk function and eIF4E phosphorylation promote cellular proliferation and survival and are critical for malignant transformation. Accordingly, Mnk inhibition may serve as an attractive cancer therapy. We now report the identification of a potent, selective and orally bioavailable Mnk inhibitor that effectively blocks 4E phosphorylation both in vitro and in vivo. In cultured cancer cell lines, Mnk inhibitor treatment induces apoptosis and suppresses proliferation and soft agar colonization. Importantly, a single, orally administered dose of this Mnk inhibitor substantially suppresses eIF4E phosphorylation for at least 4 hours in human xenograft tumor tissue and mouse liver tissue. Moreover, oral dosing with the Mnk inhibitor significantly suppresses outgrowth of experimental B16 melanoma pulmonary metastases as well as growth of subcutaneous HCT116 colon carcinoma xenograft tumors, without affecting body weight. These findings offer the first description of a novel, orally bioavailable MNK inhibitor and the first preclinical proof-of-concept that MNK inhibition may provide a tractable cancer therapeutic approach.

Topics: Animals; Antineoplastic Agents; Apoptosis; Base Sequence; Benzofurans; Blotting, Western; Cell Proliferation; Eukaryotic Initiation Factor-4E; Female; Humans; Inhibitory Concentration 50; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Mice; Mice, Nude; Molecular Sequence Data; Neoplasm Metastasis; Phosphorylation; Polymerase Chain Reaction; Protein Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Accumulating evidence indicates that the acidic microenvironments critically influence malignant behaviors of cancer including invasiveness, metastasis, and chemoresistance. Because the vacuolar-type H(+)-ATPase (V-ATPase) has been shown to cause extracellular acidification by pumping protons, we studied the role of V-ATPase in distant metastasis. Real-time PCR analysis revealed that the high-metastatic B16-F10 melanoma cells strongly expressed the a3 isoform V-ATPase compared to the low-metastatic B16 parental cells. Consistent with this, B16-F10 cells created acidic environments in lung metastases by acridine orange staining and strong a3 V-ATPase expression in bone metastases by immunohistochemistry. Immunocytochemical analysis showed B16-F10 cells expressed a3 V-ATPase not only in cytoplasm but also plasma membrane, whereas B16 parental cells exhibited its expression only in cytoplasm. Of note, knockdown of a3 V-ATPase suppressed invasiveness and migration with reduced MMP-2 and MMP-9 expression in B16-F10 cells and significantly decreased lung and bone metastases, despite that tumor growth was not altered. Importantly, administration of a specific V-ATPase a3 inhibitor FR167356 reduced bone metastasis of B16-F10 cells. These results suggest that a3 V-ATPase promotes distant metastasis of B16-F10 cells by creating acidic environments via proton secretion. Our results also suggest that inhibition of the development of cancer-associated acidic environments by suppressing a3 V-ATPase could be a novel therapeutic approach for the treatment of cancer metastasis.

Topics: Animals; Benzamides; Benzofurans; Bone Neoplasms; Cell Proliferation; Lung Neoplasms; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Melanoma, Experimental; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Tumor Microenvironment; Vacuolar Proton-Translocating ATPases; Wound Healing

Prostaglandin endoperoxide H synthases and their arachidonate products have been implicated in modulating angiogenesis during tumor growth and chronic inflammation. Here we report the involvement of thromboxane A(2), a downstream metabolite of prostaglandin H synthase, in angiogenesis. A TXA(2) mimetic, U46619, stimulated endothelial cell migration. Angiogenic basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) increased TXA(2) synthesis in endothelial cells three- to fivefold. Inhibition of TXA(2) synthesis with furegrelate or CI reduced HUVEC migration stimulated by VEGF or bFGF. A TXA(2) receptor antagonist, SQ29,548, inhibited VEGF- or bFGF-stimulated endothelial cell migration. In vivo, CI inhibited bFGF-induced angiogenesis. Finally, development of lung metastasis in C57Bl/6J mice intravenously injected with Lewis lung carcinoma or B16a cells was significantly inhibited by thromboxane synthase inhibitors, CI or furegrelate sodium. Our data demonstrate the involvement of TXA(2) in angiogenesis and development of tumor metastasis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Chemotaxis; Dinoprost; Dinoprostone; Endothelial Growth Factors; Endothelium, Vascular; Enzyme Inhibitors; Epoprostenol; Fatty Acids, Unsaturated; Fibroblast Growth Factor 2; Humans; Hydrazines; Lung Neoplasms; Lymphokines; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Rats; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase; Umbilical Veins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

In recent publications dopamine-D2 receptor scintigraphy with benzamides was postulated for specific imaging of melanoma. In a prospective study the value of 123I-iodobenzofuran (IBF), a highly specific and affine dopamine-D2 receptor ligand was evaluated for the detection of melanoma metastases. With IBF-D2 receptor scintigraphy only 2 of 17 melanoma metastases could be detected. The interpretation of the abdomen was impaired by the hepatobiliary and renal excretion of the radionuclide. The ratio striatum/frontal cortex of 2.75 +/- 0.49 3 h p.i. demonstrated a high D2-receptor binding of the ligand. IBF-D2-receptor scintigraphy is not suitable as a method of staging melanoma.

Topics: Adult; Aged; Benzofurans; Brain Neoplasms; Corpus Striatum; Female; Frontal Lobe; Humans; Iodine Radioisotopes; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prospective Studies; Radionuclide Imaging; Receptors, Dopamine D2; Sensitivity and Specificity