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Novel 3'-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3'-deoxythymidine analogues (

Drug resistance is a major problem in cancer therapy with cisplatin. It has not been reported that pleiotrophin, which is anti-apoptotic in some cancer cells, is associated with cisplatin resistance. Pleiotrophin was exogenously expressed in 293 cells. Viability and apoptosis of PC3 cells treated with different concentrations of cisplatin in the presence or absence of purified pleiotrophin were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. PC3 cells transfected with shRNAs were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting 24 h after transfection. MTT assay data indicated that the EC50 value of cisplatin for PC3 cells was significantly increased in the presence of pleiotrophin. Flow cytometry data demonstrated the pleiotrophin dose-dependent anti-apoptosis in PC3 cells treated with cisplatin. Knockdown of pleiotrophin with sh-RNA, as justified by RT-PCR and western blotting analysis, led to increased cisplatin induced-apoptosis in PC3 cells with an increased level of the cleaved poly ADP-ribose polymerase protein. Pleiotrophin may be a potential antiapoptotic protein associated with cisplatin susceptibility, which warrants further study on the role of pleiotrophin in cisplatin resistance.

PURPOSE Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501 ). PATIENTS AND METHODS Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by KIT/ platelet-derived growth factor α mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures. RESULTS Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; KIT exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; KIT exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib ( KIT exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal P = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal P = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% v 65.6%, nominal P < .0001), and better scores on patient-reported outcome measures of tolerability. CONCLUSION Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib.

Protein tyrosine phosphatases function in dephosphorylating target proteins to regulate signaling pathways that control a broad spectrum of fundamental physiological and pathological processes. Detailed knowledge concerning the roles of classical PTPs in human cancer merits in-depth investigation. We comprehensively analyzed the regulatory mechanisms and clinical relevance of classical PTPs in more than 9000 tumor patients across 33 types of cancer. The independent datasets and functional experiments were employed to validate our findings. We exhibited the extensive dysregulation of classical PTPs and constructed the gene regulatory network in human cancer. Moreover, we characterized the correlation of classical PTPs with both drug-resistant and drug-sensitive responses to anti-cancer drugs. To evaluate the PTP activity in cancer prognosis, we generated a PTPscore based on the expression and hazard ratio of classical PTPs. Our study highlights the notable role of classical PTPs in cancer biology and provides novel intelligence to improve potential therapeutic strategies based on pTyr regulation.

Natural products have been widely considered as an important resource for new drugs or lead compounds. Sinomenine (SIN) and its derivatives exert antitumor activity via regulation of inflammatory mediators. For these reasons we synthesized three series of SIN derivatives (compounds 4 a-i, 7 a-c and 11 a-c) as antitumor agents from this natural product. All compounds were prepared by modification at the C1 and C4 positions of the A ring, the C4 position of the A ring, and the C6 and C7 positions of the C ring, respectively. All the derivatives were subjected to in vitro antitumor activity against HeLa, A549, HepG-2, MCF-7 and HT-29 cell lines. To observe the apoptotic induction of SIN derivatives and its mechanism, fluorescent staining and western blot assays were carried out for active compound against MCF-7. Based on the screening results, most of the SIN derivatives showed better antitumor activity than SIN. Some of them were found to possess broad-spectrum antitumor activity. Most notably, 11 c exhibited obvious antitumor activity in both cell lines with IC

With the advent of chemical strategies that allow the design of smart bioconjugates, peptide- and protein-drug conjugates are emerging as highly efficient therapeutics to overcome limitations of conventional treatment, as exemplified by antibody-drug conjugates (ADCs). While targeting peptides serve similar roles as antibodies to recognize overexpressed receptors on diseased cell surfaces, peptide-drug conjugates suffer from poor stability and bioavailability due to their low molecular weights. Through a combination of a supramolecular protein-based assembly platform and a pH-responsive linker, the authors devise herein the convenient assembly of a trivalent protein-drug conjugate. The conjugate should ideally possess distinct features of ADCs such as 1) recognition sites that recognize cell receptor and are arranged on 2) distinct locations on a high molecular weight protein scaffold, 3) a stimuli-responsive linker, as well as 4) an attached payload such as a drug molecule. These AD-like conjugates target cancer cells that overexpress somatostatin receptors, can enable controlled release in the microenvironment of cancer cells through a new pH-responsive biotin linker, and exhibit stability in biological media.

Underwater adhesion is a great challenge for the development of adhesives as the attractive interfacial intermolecular interactions are usually weakened by the surface hydration layer. The coacervation process of sessile organisms like marine mussels and sandcastle worms has inspired substantial research interest in the fabrication of long-lasting underwater adhesives, but they generally suffer from time-consuming curing triggered by surrounding environmental changes and cannot reserve the adhesiveness once damaged. Herein, an instant and repeatable underwater adhesive was developed based on the coacervation of tannic acid (TA) and poly(ethylene glycol)77-b-poly(propylene glycol)29-b-poly(ethylene glycol)77 (PEG-PPG-PEG, F68), which was driven by hydrogen-bonding interaction, and the hydrophobic cores of F68 micelles offered an additional cross-linking to enhance the mechanical properties. The TA-F68 coacervates could be facilely painted on different substrates, exhibiting robust and instant underwater adhesion (with adhesion strength up to 1.1 MPa on porcine skin) and excellent repeatability (at least 1000 cycles), superior to the previously reported coacervates. Due to the biological activities of TA, the underwater adhesive displayed innate anticancer and antibacterial properties against different types of cancer cells and bacteria, showing great potential for diverse biomedical applications, such as injectable drug carriers, tissue glues, and wound dressings.

The use of conventional chemotherapy often faces limitations such as severe side effects, weak tumor tissue specificity, and the development of multidrug resistance. To conquer these challenges, numerous novel drug carriers have been designed in recent years. However, due to the complex processes of tumor development, metastasis and recurrence, single chemotherapy cannot fulfill the goals of clinical diverse treatment. In this work, by utilizing the inherent characteristics of surface-modified erythrocyte and the outstanding photothermal conversion capability of polydopamine (PDA), we designed and constructed a biomimetic multifunctional nanomedicine DPPR NPs to codeliver chemotherapeutic agent doxorubicin (DOX) and oxygen. The results showed that DPPR NPs exhibited inspiring features including nanoscale droplet size, good physicochemical stability, and sustained, pH-, and NIR triggered drug release behavior. It can dramatically prolong the systematic circulation time and elevated the drug accumulated level in the tumor site. Moreover, DPPR NPs could be effectively internalized into tumor cells and destroyed the intracellular redox balance to mediate cell apoptosis. It exerted excellent in vivo tumor targeting effect, photothermal conversion efficiency, ultrasound imaging responses, antitumor efficacy, and good compatibility. In summary, DPPR NPs provide a biomimetic drug delivery platform to organically combine chemotherapy and photothermal therapy for precise cancer treatment.

High heterogeneity of hepatocellular carcinoma (HCC) tumor has become an obstacle to select effective therapy for the treatment of HCC patients. Methods that can guide the decision on therapy choice for HCC treatment are highly demanded. Evaluating the drug response of heterogeneous tumor cells at the molecular level can help to reveal the toxicity mechanism of anticancer drugs and provide more information than current cell-based chemosensitivity assays. In the present work, nanostructure-assisted laser desorption/ionization mass spectrometry (NALDI-MS) was used to investigate the lipid response of HCC cells to anticancer drugs. Three types of HCC cells (LM3, Hep G2, Huh7) were treated with sorafenib, doxorubicin hydro-chloride, and cisplatin. We found that the lipid profiles of HCC cells changed a lot after the drug treatment, and the degree of lipid changes was related to the cell viability. Two pairs of fatty acids C16:1/C16:0 and C18:1/C18:0 were found to be strongly related to the viability of HCC cells after drug treatment, and were more sensitive than Methyl-thiazolyl tetrazolium (MTT) assay. Accordingly, they can act as sensitive and comprehensive indexes to evaluate the drug susceptibility of HCC cells. In addition, the peak ratio of several neighboring phospholipids displayed high correlation with drug response of specific cell subtype to specific drug. The ratio of neighboring lipids may be traced back to the activity of enzyme and gene expression which regulate the lipidomic pathway. This method provides drug response of heterogenous tumor cells at molecular level and could be a potential candidate to precise tumor chemosensitivity assay.

Fulvestrant is an FDA-approved drug with a dual mechanism of action (MOA), acting as a full antagonist and degrader of the estrogen receptor protein. A significant limitation of fulvestrant is the dosing regimen required for efficacy. Due to its high lipophilicity and poor pharmacokinetic profile, fulvestrant needs to be administered through intramuscular injections which leads to injection site soreness. This route of administration also limits the dose and target occupancy in patients. We envisioned a best-in-class molecule that would function with the same dual MOA as fulvestrant, but with improved physicochemical properties and would be orally bioavailable. Herein we report our progress toward that goal, resulting in a new lead GNE-502 which addressed some of the liabilities of our previously reported lead molecule GNE-149.