Identification of a 3,3-difluorinated tetrahydropyridinol compound as a novel antitumor agent for hepatocellular carcinoma acting via cell cycle arrest through disturbing CDK7-mediated phosphorylation of Cdc2
SummaryTetrahydropyridinol derivatives were recently reported to exhibit good biological activities, and the incorporation of fluorine into organic molecules may have profound effects on their physical and biological properties. Therefore, we investigated the anticancer activities of six fluorinated tetrahydropyridinol derivatives that we synthesized previously. We found that only one compound, 3,3-difluoro-2,2-dimethyl-1,6-diphenyl-5-tosyl-1,2,3,6-tetrahydropyridin-4-ol, showed significant antiproliferative activity on human hepatocellular carcinoma HepG2 and HMCCLM3 cells (the IC50 values were 21.25 and 29.07  μM...
Source: Investigational New Drugs - May 11, 2019 Category: Drugs & Pharmacology Source Type: research

A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma
Conclusion At 15  mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug. (Source: Investigational New Drugs)
Source: Investigational New Drugs - May 7, 2019 Category: Drugs & Pharmacology Source Type: research

Randomized phase II trial of neoadjuvant everolimus in patients with high-risk localized prostate cancer
Conclusions Neoadjuvant everolimus given at 5  mg or 10 mg daily for 8 weeks prior to radical prostatectomy did not impact pathologic responses and surgical outcomes of patients with high-risk prostate cancer.Trial registrationNCT00526591. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 30, 2019 Category: Drugs & Pharmacology Source Type: research

A phase 1 study of oral ASP5878, a selective small-molecule inhibitor of fibroblast growth factor receptors 1 –4, as a single dose and multiple doses in patients with solid malignancies
This study investigated safety, tolerability, and antitumor effect of single and multiple oral doses of ASP5878 in patients with solid tumors. This phase 1, open label, first-in-human study comprised dose-escalation and dose-expansion parts. Primary objectives of the dose-escalation part were to identify the dose-limiting toxicity (DLT), maximum tolerated dose, and recommended dose of ASP5878 for the dose-expansion part. Nine dose cohorts of ASP5878 were evaluated (0.5 ─2 mg once daily; 2─40 mg twice daily [BID]). A single dose of ASP5878 was followed by a 2-day pharmacokinetic collection, and then either 28-...
Source: Investigational New Drugs - April 30, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: Sphingadienes show therapeutic efficacy in neuroblastoma in vitro and in vivo by targeting the AKT signaling pathway
The authors would like to note an omission of disclosure in this paper. Author JDS is cofounder, equity-holder, and consultant of GILTRx Therapeutics. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 29, 2019 Category: Drugs & Pharmacology Source Type: research

Anticancer activity, apoptosis and a structure –activity analysis of a series of 1,4-naphthoquinone-2,3-bis-sulfides
SummaryWe have previously reported on the synthesis of 1,4-naphthoquinone-sulfides and in this investigation we report on their anticancer activity against 6 human cancer cell lines to evaluate their cytostatic effects. The 1,4-naphthoquinone-2,3-bis-sulfides were most effective against melanoma (UACC62) (GI50 = 6.5–10 μM) and prostate (PC3) (GI50 = 5.51–8.53 μM) cancer cell lines. They exhibited better cytostatic effects than etoposide (GI50 = 0.56–36.62 μM), parthenolide (GI50 = 3.58–25.97 μM) and VK3 (GI50&thi...
Source: Investigational New Drugs - April 27, 2019 Category: Drugs & Pharmacology Source Type: research

Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors
Conclusions Ivosidenib demonstrated good oral exposure and a long half-life. Robust, persistent plasma 2-HG inhibition was observed in IDH1-mutant cholangiocarcinoma and chondrosarcoma. Ivosidenib 500  mg QD is an appropriate dose irrespective of various intrinsic and extrinsic factors.Trial RegistrationClinicalTrials.gov (NCT02073994). (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 26, 2019 Category: Drugs & Pharmacology Source Type: research

The metronomic all-oral DEVEC is an effective schedule in elderly patients with diffuse large b-cell lymphoma
Conclusion The favourable activity of DEVEC compared to a real-life series and the convenience of an oral administration, may possibly lay the groundwork for a paradigm-shift in the treatment of elderly DLBCL. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 26, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: Eribulin, trastuzumab, and pertuzumab as first-line therapy for patients with HER2-positive metastatic breast cancer: a phase II, multicenter, collaborative, open-label, single-arm clinical trial
The authors would like to note the replacement of Fig.  2b, for which Fig. 2a was placed erringly, with appropriate Fig. 2b. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 25, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of the anti-heparin-binding epidermal growth factor-like growth factor antibody U3-1565 with cetuximab in patients with cetuximab- or panitumumab-resistant metastatic colorectal cancer
SummaryKRAS wild-type colorectal cancers initially responsive to anti-endothelial growth factor receptor (EGFR) antibodies [cetuximab (Cetu)/panitumumab (Pani)] develop acquired resistance. Overexpression of EGFR ligands such as heparin-binding EGF-like growth factor (HB-EGF) may be one resistance mechanism. This phase I study of U3-1565, anti-HB-EGF antibody, and Cetu combination therapy enrolled patients withKRAS wild-type metastatic colorectal cancer who had received two ≤ regimens with fluoropyrimidine, oxaliplatin, irinotecan, and Cetu/Pani and had disease progression on Cetu/Pani. Recommended dose (RD) was determi...
Source: Investigational New Drugs - April 24, 2019 Category: Drugs & Pharmacology Source Type: research

Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors
Conclusions Cobimetinib and pictilisib combination therapy in patients with solid tumors had limited tolerability and efficacy. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 24, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma
The authors would like to note an error in Figures  1 and 2 of this paper. The graph in Figure 1 incorrectly reflected the overall survival (OS), when it should have displayed the progression-free survival (PFS). The caption and median PFS values were correct. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 24, 2019 Category: Drugs & Pharmacology Source Type: research

A phase 2, open-label study of brentuximab vedotin in patients with CD30-expressing solid tumors
Conclusion The safety profile of BV in patients with solid tumors was similar to the known safety profile of BV. In solid tumors, BV had modest activity as a single agent, which was similar to other second-line treatments already available to patients. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 16, 2019 Category: Drugs & Pharmacology Source Type: research

Midkine silencing enhances the anti –prostate cancer stem cell activity of the flavone apigenin: cooperation on signaling pathways regulated by ERK, p38, PTEN, PARP, and NF-κB
In conclusion, MK-regulated events are different between PCSCs, and when combined with apigenin plus MK silencing, docetaxel treatment may be a valuable approach for the eradication of PCSCs. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 16, 2019 Category: Drugs & Pharmacology Source Type: research

A preclinical evaluation of thiostrepton, a natural antibiotic, in nasopharyngeal carcinoma
Conclusion Thiostrepton effectively suppressed NPC cell proliferation, migration, and invasion, likely by several mechanisms. Thiostrepton may be a potential therapeutic agent for treating NPC in the future. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 16, 2019 Category: Drugs & Pharmacology Source Type: research

Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR 2 and miR-34a
SummaryThe pharmacokinetic (PK) and potential effects ofEmodin on liver cancer were systematically evaluated in this study. Both the intragastric administration (i.g.) and hypodermic injection (i.h.) ofEmodin exhibited a strong absorption (absorption rate  human> beagle dog. These PK data provided the basis for the subsequent animal experiments. In liver cancer patient tissues, the expression of vascular endothelial growth factor (VEGF)-induced signaling pathways, including phosphorylated VEGF receptor 2 (VEGFR2), AKT, and ERK1/2,were simultaneously elevated, but miR-34a expression was reduced and negatively corr...
Source: Investigational New Drugs - April 11, 2019 Category: Drugs & Pharmacology Source Type: research

Safety and clinical activity of the Notch inhibitor, crenigacestat (LY3039478), in an open-label phase I trial expansion cohort of advanced or metastatic adenoid cystic carcinoma
Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 6, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: A novel histone deacetylase inhibitor, CG200745, potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1 and Bcl- XL
The blots of control and docetaxel for caspase-9, caspase-3, caspase-8, Bcl-XL, and tubulin in the Figure 4f were reused from Figure 4 of our previous paper published inJournal of Urology in 2010 (https://doi.org/10.1016/j.juro.2010.07.035). (Source: Investigational New Drugs)
Source: Investigational New Drugs - April 2, 2019 Category: Drugs & Pharmacology Source Type: research

Emodin induced necroptosis in the glioma cell line U251 via the TNF- α/RIP1/RIP3 pathway
This study aimed to investigate the effects and mechanisms of emodin-induced necroptosis in the glioma cell line U251 by targeting the TNF- α/RIP1/RIP3 signaling pathway. We found that emodin could significantly inhibit U251 cell proliferation, and the viability of U251 cells treated with emodin was reduced in a dose- and time-dependent manner. Flow cytometry assays and Hoechst-PI staining assays showed that emodin induced apoptosis an d necroptosis. Real-time PCR and western blot analysis showed that emodin upregulated the levels of TNF-α, RIP1, RIP3 and MLKL. Furthermore, the RIP1 inhibitor Nec-1 and the RIP3...
Source: Investigational New Drugs - March 28, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: Phase II study of sunitinib in Japanese patients with unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumor
In the original publication of this article, the license subtype should be CC BY and not CC BY-NC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 23, 2019 Category: Drugs & Pharmacology Source Type: research

Discovery of a pyrimidine compound endowed with antitumor activity
SummaryRecently, some synthetic nitrogen-based heterocyclic molecules, such as PJ34, have shown pronounced antitumor activity. Therefore, we designed and synthesized new derivatives characterized by a nitrogen-containing scaffold and evaluated their antiproliferative properties in tumor cells. We herein report the effects of three newly synthesized compounds on cell lines from three different human cancers: triple-negative breast cancer, colon carcinoma and glioblastoma. We found that two of these compounds did not affect proliferation, while the third significantly inhibited replication of the three cell lines. Moreover, ...
Source: Investigational New Drugs - March 21, 2019 Category: Drugs & Pharmacology Source Type: research

The exosome secretion inhibitor neticonazole suppresses intestinal dysbacteriosis-induced tumorigenesis of colorectal cancer
SummaryColorectal cancer (CRC) is the most frequently encountered malignancy associated with the rectum or colon, and accumulating evidences have implicated intestinal dysbacteriosis (IDB, disruption of gut microbiome) and exosomes in the pathology of CRC. We aimed to investigate the effect of IDB on exosome secretion in a CRC xenograft mouse model. An IDB mouse model was established and was inoculated with the CRC cell line SW480 as a xenograft tumor. Tumor growth was monitored for 15  days in sham and IDB mice, after which blood was collected to assess serum exosome secretion. A novel exosome secretion inhibitor, ne...
Source: Investigational New Drugs - March 19, 2019 Category: Drugs & Pharmacology Source Type: research

A phase I, dose-escalation study of PF-06650808, an anti-Notch3 antibody –drug conjugate, in patients with breast cancer and other advanced solid tumors
Conclusions The anti-Notch3 ADC PF-06650808 has demonstrated a manageable safety profile and early signs of antitumor activity in patients with advanced BC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 18, 2019 Category: Drugs & Pharmacology Source Type: research

Cytotoxicity of [HuArgI (co)-PEG5000]-induced arginine deprivation to ovarian Cancer cells is autophagy dependent
In this study, we assess arginine auxotrophy in ovarian cancer cells and attempt to target them using arginine deprivation induced by a pegylated recombinant human Arginase I cobalt [HuArgI (Co)-PEG5000]. Ovarian cancer cells were sensitive to [HuArgI (Co)-PEG5000]-induced arginine deprivation with IC50 values in the low pM range. Addition of excess L-citrulline rescued only one of three cell lines tested, indicating that the majority of cell lines are completely auxotrophic for arginine. The expression pattern of argininosuccinate synthetase (ASS1) confirmed the degree of auxotrophy of ovarian cancer cell lines with compl...
Source: Investigational New Drugs - March 18, 2019 Category: Drugs & Pharmacology Source Type: research

Tubulin colchicine site binding agent LL01 displays potent antitumor efficiency both in vitro and in vivo with suitable drug-like properties
In this study, we further demonstrated that LL01 was not a P-gp substrate. It potently inhibited the growth of a variety of tumor cells, including those with multidrug resistance, with GI50 values in the low nanomole ranges. In vitro liver microsome stability assay, LL01 was modest stable in the liver microsomes of human, mouse and rat, but was fast metabolized in dog. After single oral administration of LL01 at a dose of 10  mg/kg in SD male rats, LL01 showed acceptable PK properties with a mean bioavailability of 41%. In human HepG2 hepatoma xenograft, at the oral doses of 25 mg/kg/day and 12.5 mg/kg/day, ...
Source: Investigational New Drugs - March 18, 2019 Category: Drugs & Pharmacology Source Type: research

Knockdown of FBXO22 inhibits melanoma cell migration, invasion and angiogenesis via the HIF-1 α/VEGF pathway
This study investigated the effect of FBXO22 on melanoma angiogenesis, migration, and invasion. Results showed that FBXO22 staining intensity was increased in malignant melanoma (MM) compared with that in skin tissue (P˂0.001). The percentage of high FBXO22 expression in MM (74.3%) was markedly higher than that in paracancerous and skin tissues (0%) (P˂0.001). FBXO22 was also overexpressed in MM tissues compared with that in normal skin tissues. FBXO22 knockdown in vitro inhibited MM cell migration, invasion, and angiogenesis (P 
Source: Investigational New Drugs - March 18, 2019 Category: Drugs & Pharmacology Source Type: research

Ramucirumab as a second line therapy for advanced HCC: a significant achievement or a wasted opportunity for personalised therapy?
This study will also critically assess the gaps in a previous negative phase III trial that tested other potentially useful treatments and suggest ways to modernise clinical trials and personalise therapy for advanced HCC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 16, 2019 Category: Drugs & Pharmacology Source Type: research

Identification of inhibitors of the polo-box domain of polo-like kinase 1 from natural and semisynthetic compounds
In conclusion, we identified four new chemical scaffolds that may serve as lead compounds for the development of selective PLK1 inhibitors in the future. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 15, 2019 Category: Drugs & Pharmacology Source Type: research

Novel palladium (II) complexes with tetradentate thiosemicarbazones. Synthesis, characterization, in vitro cytotoxicity and xanthine oxidase inhibition
SummaryIn vitro cytotoxicity and xanthine oxidase inhibition capabilities were investigated for five palladium (II) chelate complexes. The palladium complexes were synthesized by starting from S-alkyl-thiosemicarbazones where the alkyl component is methyl, ethyl, propyl or butyl. The solid complexes are characterized by elemental analysis and spectroscopic techniques (UV-visible, IR and 1H NMR). In order to be able to verify the N2O2-type thiosemicarbazidato ligand (L2 −) structure in the square planar geometry, complex 1 has been studied as a representative by using single crystal X-ray crystallography. The in vitro...
Source: Investigational New Drugs - March 14, 2019 Category: Drugs & Pharmacology Source Type: research

Eribulin, trastuzumab, and pertuzumab as first-line therapy for patients with HER2-positive metastatic breast cancer: a phase II, multicenter, collaborative, open-label, single-arm clinical trial
Conclusions ETP therapy showed acceptable efficacy and safety and is a potential first-line therapy for patients with HER2-positive MBC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 8, 2019 Category: Drugs & Pharmacology Source Type: research

Increased DKC1 expression in glioma and its significance in tumor cell proliferation, migration and invasion
SummaryThe dyskeratosis congenita 1 (DKC1) gene is located on the X chromosome at Xq28. Dyskerin encoded by the DKC1 gene is associated with the formation of certain small RNAs and the telomerase activity. Inherited mutations in DKC1 inactivate the dyskerin and causes dyskeratosis congenital, which is characterized by skin defects, hematopoiesis failure, and increased susceptibility to cancer. DKC1 reportedly up-regulates in several human cancers, including renal cell carcinoma and prostate cancer. Dyskerin is deregulated in B-chronic lymphocytic leukemia and breast carcinomas, but its expression and function in glioma hav...
Source: Investigational New Drugs - March 7, 2019 Category: Drugs & Pharmacology Source Type: research

A phase I study to determine the maximum tolerated dose of trifluridine/tipiracil and oxaliplatin in patients with refractory metastatic colorectal cancer: LUPIN study
Conclusions A combination of FTD/TPI 35  mg/m2 bid on days 1 –5 and 15–19 and oxaliplatin 85 mg/m2 on days 1 and 15 every 4  weeks could be a suitable regimen for the recommended dose of FTD/TPI plus oxaliplatin in patients with refractory mCRC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 6, 2019 Category: Drugs & Pharmacology Source Type: research

A high-throughput drug screen identifies auranofin as a potential sensitizer of cisplatin in small cell lung cancer
SummarySmall cell lung cancer (SCLC) is a highly lethal malignancy with the 5-year survival rate of less than 7%. Chemotherapy-resistance is a major challenge for SCLC treatment in clinic. In the study, we developed a high-throughput drug screen strategy to identify new drugs that can enhance the sensitivity of chemo-drug cisplatin in SCLC. This screen identified auranofin, a US Food and Drug Administration (FDA)-approved drug used therapeutically for rheumatoid arthritis, as a sensitizer of cisplatin. Further study validated that auranofin synergistically enhanced the anti-tumor activity of cisplatin in chemo-resistant SC...
Source: Investigational New Drugs - March 2, 2019 Category: Drugs & Pharmacology Source Type: research

A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors
Conclusions This was the first study to evaluate pexidartinib in Asian patients with advanced solid tumors. Pexidartinib was safe and tolerable in this population at the recommended phase 2 dose previously determined for Western patients (funded by Daiichi Sankyo;clinicaltrials.gov number, NCT02734433). (Source: Investigational New Drugs)
Source: Investigational New Drugs - March 2, 2019 Category: Drugs & Pharmacology Source Type: research

Population pharmacokinetic analysis of AR-67, a lactone stable camptothecin analogue, in cancer patients with solid tumors
Conclusions A POP PK model was developed to characterize AR-67 pharmacokinetics and identified age as a significant covariate. Exposure PK metrics Cmax and AUC were shown to predict hematological toxicity. Further efforts to identify clinically relevant determinants of AR-67 disposition and effects in a larger patient population are warranted. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 28, 2019 Category: Drugs & Pharmacology Source Type: research

Axitinib pharmacologic therapeutic monitoring reveals severe under-exposure despite titration in patients with metastatic renal cell carcinoma
Conclusion We report a patient with significant axitinib under-exposure, possibly due to a poor absorption. PTM should be evaluated and considered in drug developments evaluating combination therapies based on axitinib. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 26, 2019 Category: Drugs & Pharmacology Source Type: research

A phthalimidoalkanamide derived novel DNMT inhibitor enhanced radiosensitivity of A549 cells by inhibition of homologous recombination of DNA damage
SummaryPurpose To elucidate the radiosensitizing effect and underlying mechanism of a new kind of DNA methyltransferase (DNMT) inhibitor with biological availability.Methods A novel non-nucleoside compound, designated as MA-17, was recently derived from a phthalimido alkanamide structure. DNMT expressions were confirmed in cultured human lung cancer (A549) and normal astrocyte (NHA) cells, radiosensitivity was measured using clonogenic assay, and assays of cell cycle alteration, apoptosis, DNA damage repair, and differential gene expression were undertaken.Results MA-17 significantly radiosensitized A549 cells with a mean ...
Source: Investigational New Drugs - February 22, 2019 Category: Drugs & Pharmacology Source Type: research

Switch maintenance therapy with S-1 after induction therapy with carboplatin and nanoparticle albumin-bound paclitaxel in advanced lung squamous cell carcinoma
Conclusions Switch maintenance therapy with S-1 after induction therapy with carboplatin andnab-paclitaxel was associated with moderate efficacy and acceptable safety and may represent a feasible treatment option for patients with advanced SCC. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 21, 2019 Category: Drugs & Pharmacology Source Type: research

Durable response to the ALK inhibitor alectinib in inflammatory myofibroblastic tumor of the head and neck with a novel SQSTM1 –ALK fusion: a case report
This report highlights the possibility of alectinib being a reasonable option for advanced IMT with theSQSTM1-ALK fusion. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 21, 2019 Category: Drugs & Pharmacology Source Type: research

Phase I study of TAS-121, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with non-small-cell lung cancer harboring EGFR mutations
Conclusions TAS-121 was well tolerated up to the MTD and demonstrated antitumor activity in Japanese T790M-positive NSCLC patients.Clinical trial registration: JapicCTI-142651. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 21, 2019 Category: Drugs & Pharmacology Source Type: research

Synergistic effect and reduced toxicity by intratumoral injection of cytarabine-loaded hyaluronic acid hydrogel conjugates combined with radiotherapy on lung cancer
SummaryThe aim of this study was to explore the synergistic anti-tumor effects of cytarabine hyaluronic acid-tyramine (Ara-HA-Tyr) hydrogel conjugates and radiotherapy (RT) in the Lewis lung cancer (LLC) xenograft model, and the mechanisms involved. The radiotherapy sensitization ratio (SER) of 0.5  μg cytarabine (Ara-C) was 1.619 in the LLC cells. Ara-HA-Tyr was prepared by encapsulating Ara-C into hyaluronic acid-tyramine (HA-Tyr) conjugates. The hydrogels were formed through the oxidative coupling of tyramines by hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). Mice engrafted with the LLC cells were gi...
Source: Investigational New Drugs - February 21, 2019 Category: Drugs & Pharmacology Source Type: research

GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma
SummaryAmong the acquired modifications in cancer cells, changes in lysosomal phenotype and functions are well described, making lysosomes a potential target for novel therapies. Some weak base lipophilic drugs have a particular affinity towards lysosomes, taking benefits from lysosomal trapping to exert anticancer activity. Here, we have developed a new lysosomotropic small molecule, GNS561, and assessed its activity in multiple in vitro intrahepatic cholangiocarcinoma models (HuCCT1 and RBE cell lines and patient-derived cells) and in a chicken chorioallantoic membrane xenograft model. GNS561 significantly reduced cell v...
Source: Investigational New Drugs - February 19, 2019 Category: Drugs & Pharmacology Source Type: research

An orally antitumor chalcone hybrid inhibited HepG2 cells growth and migration as the tubulin binding agent
SummaryLiver cancer is a kind of high mortality cancer due to the difficulty of early diagnosis. It is necessary to develop the anticancer agents to treat liver cancer. Here, a novel chalcone derivative was synthesized and evaluated for anticancer activity in vitro against liver cancer cell lines (HepG2, SNU-423, SMMC7221, and SNU-398). The chalcone hybrid9 displayed the antiproliferative effect against HepG2, SNU-423, SMMC7221 and SNU-398 cells with IC50 values of 0.9  μM, 2.7 μM, 6.2 μM and 4.6 μM, respectively. Cellular mechanisms showed that derivative9 could obviously inhibit HepG2 cell...
Source: Investigational New Drugs - February 11, 2019 Category: Drugs & Pharmacology Source Type: research

LEF1-AS1 contributes to proliferation and invasion through regulating miR-544a/ FOXP1 axis in lung cancer
This study aims to investigate the potential role oflncRNALEF1-AS1, in the progression of lung cancer. Quantitative real-time PCR (qRT-PCR) and western blot assays showed that LEF1-AS1 was upregulated while miR-544a was downregulated in lung cancer specimens and cells. Overexpression of LEF1-AS1 led to the enhancement of cell proliferation and invasion, revealed by CCK-8 assay and transwell assay. A negative correlation was found between LEF1-AS1 and miR-544a. BLAST analysis and dual-luciferase assay confirmed that FOXP1 is a downstream effector of miR-544a. Therefore, the LEF1-AS1/miR-544a/FOXP1 axis is an important contr...
Source: Investigational New Drugs - February 8, 2019 Category: Drugs & Pharmacology Source Type: research

Delineation of proapoptotic signaling of anthracene-shelled M 2 L 4 metallacapsules and their synergistic activity with curcumin in cisplatin-sensitive and resistant tumor cell lines
In this study, we provide an oncopharmacological evaluation of the Pt(II)- and Pd(II)-clipped M2L4 nanocapsules; we report a thorough analysis of their synergistic effects in combined treatments with the pleiotropic anticancer agent curcumin. We examined changes in cellular expression of several apoptosis-related proteins in a panel of tumor cell lines with different chemosensitivity towards cisplatin, i.e. HT-29, HL-60 and its resistant strains HL-60/CDDP and HL-60/Dox, in order to assess the molecular mechanisms of their antitumor activity The results of the immunoassay concluded activation of the mitochondrial apoptotic...
Source: Investigational New Drugs - February 8, 2019 Category: Drugs & Pharmacology Source Type: research

A phase I study of the antibody drug conjugate ASG-5ME, an SLC44A4-targeting antibody carrying auristatin E, in metastatic castration-resistant prostate cancer
Conclusions Further development of ASG-5ME is not being pursued due to its narrow therapeutic index. Some toxicities were potentially related to on-target effects on normal tissue expressing the SLC44A4 protein. However, other toxicities were consistent with studies of previous MMAE-containing ADCs. Unconjugated MMAE is a less likely etiology based on prior data. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 6, 2019 Category: Drugs & Pharmacology Source Type: research

Clinical outcomes of advanced stage cancer patients treated with sequential immunotherapy in phase 1 clinical trials
Conclusions ICI-na ïve patients may experience improved clinical outcomes on immunotherapy-based phase 1 clinical trials than patients who have received prior ICI. This may be particularly true for patients who received prior IL-2 or IFNγ. Further development of immunotherapy combination therapies is needed to impro ve clinical outcomes of these patients. These results should be validated in a larger study. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 6, 2019 Category: Drugs & Pharmacology Source Type: research

Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo
SummaryWe generated a nitric oxide (NO)-releasing derivative of the anti-HIV protease inhibitor lopinavir by linking the NO moiety to the parental drug. We investigated the effects of lopinavir and its derivative lopinavir-NO on melanoma cell lines in vitro and in vivo. Lopinavir-NO exhibited a twofold stronger anticancer action than lopinavir in vitro. These results were successfully translated into syngeneic models of melanoma in vivo, where a significant reduction in tumour volume was observed only in animals treated with lopinavir-NO. Both lopinavir and lopinavir-NO inhibited cell proliferation and induced the trans-di...
Source: Investigational New Drugs - February 1, 2019 Category: Drugs & Pharmacology Source Type: research

Apatinib, a novel VEGFR inhibitor plus docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR: a phase I trial
Conclusion Apatinib plus docetaxel was well tolerated and showed promising efficacy in advanced lung adenocarcinoma. This combination therapy may represent a potent therapeutic option for advanced lung adenocarcinoma patients with wild-type EGFR. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 1, 2019 Category: Drugs & Pharmacology Source Type: research

Modified ingenol semi-synthetic derivatives from Euphorbia tirucalli induce cytotoxicity on a large panel of human cancer cell lines
In conclusion, the semi-synthetic ingenol compounds, in particular, IngC, demonstrated a potent antitumor activity on all cancer cell lines evaluated. Although the underlying mechanisms of action of IngC are not elucidated, our results provide insights for further studies suggesting IngC as a putative therapy for cancer treatment. (Source: Investigational New Drugs)
Source: Investigational New Drugs - February 1, 2019 Category: Drugs & Pharmacology Source Type: research