High Antitumor Activity Research Articles

Glycopolymers Mediate Suicide Gene Therapy in ASGPR-Expressing Hepatocellular Carcinoma Cells in Tandem with Docetaxel.

Cationic glycopolymers stand out as gene delivery nanosystems due to their inherent biocompatibility and high binding affinity to the asialoglycoprotein receptor (ASGPR), a target receptor overexpressed in hepatocellular carcinoma (HCC) cells. However, their synthesis procedure remains laborious and complex, with problems of solubilization and the need for protection/deprotection steps. Here, a mini-library of well-defined poly(2-aminoethyl methacrylate hydrochloride-co-poly(2-lactobionamidoethyl methacrylate) (PAMA-co-PLAMA) glycopolymers was synthesized by activators regenerated by electron transfer (ARGET) ATRP to develop an efficient gene delivery nanosystem. The glycoplexes generated had suitable physicochemical properties and showed high ASGPR specificity and high transfection efficiency. Moreover, the HSV-TK/GCV suicide gene therapy strategy, mediated by PAMA144-co-PLAMA19-based nanocarriers, resulted in high antitumor activity in 2D and 3D culture models of HCC, which was significantly enhanced by the combination with small amounts of docetaxel. Overall, our results demonstrated the potential of primary-amine polymethacrylate-containing-glycopolymers as HCC-targeted suicide gene delivery nanosystems and highlight the importance of combined strategies for HCC treatment.

Synthesis and antiproliferative evaluation of novel 1,3,4-thiadiazole-S-alkyl derivatives based on quinazolinone

Thirty-five novel 1,3,4-thiadiazole-S-alkyl derivatives based on quinazolinone have been designed and synthesized. The structures of the target compounds 5a − 5p and 6a − 6s were confirmed by their IR, 1H NMR, 13C NMR, HR-ESI-MS spectroscopic data. This study detected their cytotoxicity for mouse fibroblast (normal cells, L929) and their in vitro antiproliferative activities against human cancer cell lines (Hela, MCF-7 and A549) by using CCK-8 assay. The results of all the tested compounds 5a − 5p and 6a − 6s showed that the growth and reproduction of cells were impeded to a certain extent. Compared with the reference drug 5-FU, some compounds even showed better proliferation inhibition against various cancer cells. Among these, most of the compounds had relatively less cytotoxicity to L929 cells. 6-Chloro-2-(2-(benzylthio)-1,3,4-thiadiazol-5-yl)-quinazolin-4(3H)-one (6a) gave expression to the strongest inhibitory activity on Hela cells with IC50 value of 1.40 µM. 6-Chloro-2-[2-(4-trifluoromethylbenzylthio)-1,3,4-thiadiazol-5-yl]-quinazolin-4(3H)-one (6s) displayed high antitumor activities against MCF-7 cells with IC50 values of 3.01 µM. 2-[2-(Benzylthio)-1,3,4-thiadiazol-5-yl]-quinazolin-4(3H)-one (5a) revealed excellent antitumor activities against A549 cells with IC50 values of 2.21 µM.

Anti-Tumor Efficacy of Photodynamic Therapy of Solid Tumors in Laboratory Animals with Guanidine and Biguanidine Derivatives of Chlorine e6.

We evaluated antitumor efficacy of photodynamic therapy of murine Ehrlich carcinoma and rat sarcoma M-1 with new photosensitizers 131-N-(4-aminobutyl)amydo chlorine e6 (1), 132-(5-guanidylbutanamido)-chlorine e6 (2), and 132-(5-biguanidylbutanamido)-chlorine e6 (3). The inhibiting effect of the photodynamic therapy was evaluated by the following parameters: tumor growth inhibition, complete regression of the tumors, and absolute growth rate of the tumor nodes in animals with the continued neoplasia growth. The criterion of cure was the absence of tumors up to 90 days after the therapy. It is shown that the studied photosensitizers have high antitumor activity in the photodynamic therapy of the Ehrlich carcinoma and sarcoma M-1.

Phase 1 trial of the anti-LAG3 antibody favezelimab plus pembrolizumab in advanced gastric cancer.

394 Background: In the dose-confirmation phase of this multicohort trial (NCT02720068), the anti-LAG-3 antibody favezelimab had a manageable safety profile and promising antitumor activity in patients (pts) with advanced solid tumors, confirming preliminary RP2D. Here we present results on the safety of favezelimab (fave) plus pembrolizumab (pembro) in all treated pts and efficacy in pts with advanced gastric cancer. Methods: In this phase 1b trial eligible pts aged ≥ 18 years were enrolled into 7 cohorts across 3 tumor types: Cohorts A (3L+ CRC), B (1L/2L CRC), C (PD-1 naïve HNSCC), D (PD-1 refractory HNSCC), E (PD-1 naïve gastric cancer), F (all solid tumors), and G (PD-1 naïve 3L CRC). Pts with gastric cancer in cohort E received either 200 mg fave + 200 mg pembro, or 700 mg fave + 200 mg pembro Q3W up to 35 cycles. Treatment continued until progression, unacceptable toxicity, or pt withdrawal. Primary endpoint was safety and tolerability of fave + pembro. Secondary endpoint was ORR per RECIST 1.1 by investigator assessment. Exploratory endpoints were PFS per RECIST 1.1, and OS. Data cutoff date was March 21, 2022. Results: At data cutoff, 397 pts were enrolled: 38 to fave, 368 to fave + pembro including 9 who crossed over from fave alone. Of these, 80 pts had gastric cancer; 50 (62.5%) of which had ≥2 lines of treatment, and 48 (60.0%) had PD-L1 CPS≥ 1. Among 368 pts treated with fave + pembro, treatment-related adverse events (TRAEs) occurred in 232 (63.0%) with fave + pembro. Grade ≥3 TRAEs occurred in 66 (17.9%) pts with fave + pembro. There were no grade 5 TRAEs. Immune-mediated adverse events (AEs) occurred in 121 (32.9%) pts with fave + pembro. Grade ≥3 immune-mediated AEs occurred in 27 (7.3%) pts with fave + pembro. No grade 5 immune-mediated AEs occurred. In pts with gastric cancer, the overall ORR was 11.3% (95% CI, 5.3-20.3 [3.8% CR; 7.5% PR]) with fave + pembro. In 2 arms, higher dose of fave (700mg) showed increased ORR and 12 months PFS rate. The table summarizes antitumor activity in the gastric cancer cohort. Conclusions: Favezelimab alone or in combination with pembrolizumab had an acceptable safety profile. The combination therapy showed antitumor activity in line with other checkpoint inhibitors in advanced gastric cancer though higher antitumor activity was seen in PDL1 CPS≥ 1 tumors, particularly at higher dose. Clinical trial information: NCT02720068 . [Table: see text]

Tislelizumab in combination with anlotinib as first-line treatment for unresectable hepatocellular carcinoma: A single-arm, phase II clinical trial.

576 Background: The inability to perform liver resection is an important cause of high mortality in Hepatocellular carcinoma (HCC) patients. Based on the clinical data of anlotinib (a multi-targeted tyrosine kinase inhibitor) and tislelizumab (anti‐PD‐1 antibody) in HCC pts, we therefore evaluated the safety and efficacy of tislelizumab plus anlotinib as first-line therapy for patients with unresectable HCC. Methods: Patients aged 18-75 years, with unresectable HCC, ECOG PS 0-3, BCLC stage A-D, Child-Pugh score A-C, and CNLC stage Ia-IV were enrolled. Patients who met the inclusion criteria received tislelizumab(intravenous drip, 200 mg/d1, Q3W) and anlotinib(oral, 8-12 mg/d1-14, Q3W). The primary endpoint was objective response rate (ORR). The secondary endpoints included disease control rate (DCR),overall survival (OS), progression-free survival (PFS), adverse events (AEs), and serious adverse events (SAEs). Results: Between Sep-2020 until Sep-2022, 37 patients were enrolled, and 25 patients’ clinical data were available to assess clinical efficacy. The median age of the pts was 62 years (ranged 31-72 years), 15 pts (60%) ECOG PS 1, 14 pts (56%) BCLC stage C, 17 pts (68%) Hepatitis B Virus Infection and 13 pts (52%) had received prior local regional therapy. The ORR per mRECIST was 32% (95% CI, 12.3%-51.7%) and DCR was 72% (95% CI, 53.1%-90.9%). The best clinical response was CR in 2 pts (8%), 6 pts (24%) PR and 10 pts (40%) SD. With a median follow-up of 12.7 months, the estimated median PFS was 11.8 months, and the median OS was not reached. The most common AEs during follow-up were AST increased (52%), γ-GT increased (48%), and hypoalbuminemia (48%). Conclusions: Tislelizumab combined with anlotinib showed high antitumor activity and good tolerability in the treatment of unresectable HCC, which may be an effective and safe treatment option.

Enhancing nanoparticle paclitaxel antitumor response through targeted inhibition of c-Met pathway by merestinib in gastric cancer models.

372 Background: Gastric adenocarcinoma (GAC) is the fifth most common malignancy and the third most common cause of cancer-related deaths worldwide. Combination chemotherapy regimens are commonly used to treat GAC, but the median survival time remains less than one year. Nanoparticle albumin-bound paclitaxel ( nab-paclitaxel, NPT), an approved treatment for breast cancer, non-small cell lung cancer and pancreatic cancer, has demonstrated high antitumor activity in previous GAC studies. Many growth factors and their receptors are overexpressed in GAC and have been implicated in its pathophysiology. Aberrant activation of the c-Met pathway has been reported in up to 50% of GAC patients. We hypothesize that merestinib, a small-molecule inhibitor of c-Met, with additional inhibition of Axl and DDR1/2 pathways, will have significant antitumor effects and will enhance nab-paclitaxel chemotherapy response in GAC preclinical models. Methods: GAC subcutaneous xenografts were established by injecting MKN-45 and SNU-1 cells in NOD/SCID mice to study treatment effects on tumor volume, tumor weight, net tumor growth, and mouse body weight. Immunohistochemistry analyses of xenograft tissues were performed using Ki67 and endomucin to examine tumor cell proliferation and microvessel density, respectively. Results: In vitro assays showed that nab-paclitaxel and merestinib decreased cell proliferation in all three GAC-associated cell lines tested, with an additive effect in combination. Reduction in cell proliferation at low doses of nab-paclitaxel (10 nM), merestinib (100 nM), and their combination was 87%, 82%, and 94% (MKN-45, high phospho-c-Met expression), 59%, 50%, and 82% (SNU-1, low phospho-c-Met expression), and 53%, 19%, and 66% in gastric fibroblasts. Immunoblot analysis of merestinib treated MKN-45 cells revealed increased expression of pro-apoptotic proteins and decreased expression of phospho-c-Met, phospho-EGFR, phospho-IGF-1R, phospho-ERK, and phospho-AKT. In gastric fibroblasts, merestinib decreased phospho-ERK and increased pro-apoptotic protein expression. Phospho-c-Met and phospho-EGFR were not detected in SNU-1 immunoblots; however, phospho-ERK, phospho-VEGFR, and apoptotic protein expression increased after treatment. In MKN-45 xenografts, net tumor growth in control, nab-paclitaxel, merestinib, and combination groups was 503 mm3, 115 mm3, 91 mm3, and -9.7 mm3. Immunohistochemistry analysis of tumor cell proliferation and microvessel density corroborated tumor growth study results. Conclusions: These findings suggest that merestinib has strong antitumor activity in GAC and exhibits an additive effect when administered with nab-paclitaxel. These results provide compelling evidence that this therapeutic approach may lead to a clinically relevant combination to improve GAC patients’ survival.

Targeted Inhibition of the HGF/c-Met Pathway by Merestinib Augments the Effects of Albumin-Bound Paclitaxel in Gastric Cancer

Background and Hypothesis: Combination chemotherapy regimens are commonly used to treat gastric adenocarcinoma (GAC), but the median survival time remains less than one year. Nab-paclitaxel has demonstrated high antitumor activity in previous GAC studies. Many growth factors and their receptors are overexpressed in GAC and have been implicated in its pathophysiology. We hypothesize that merestinib, a small-molecule inhibitor targeting c-Met, Axl, and DDR1/2 pathways, will have significant antitumor effects and will enhance the response to nab-paclitaxel in GAC preclinical models.
 Project Methods: In vitro proliferation and protein expression were assessed using WST-1 and immunoblot assays. Subcutaneous xenografts of MKN-45 and SNU-1 cell lines were implanted in mice to study tumor growth inhibition. Immunohistochemistry was performed to examine intratumor proliferation and microvessel density.
 Results: In vitro assays showed that nab-paclitaxel and merestinib decreased cell proliferation in all three cell lines, with an additive effect in combination. Reduction in cell proliferation at low doses of nab-paclitaxel (10 nM), merestinib (100 nM), and their combination was 87%, 82%, and 94% (MKN-45 cell line, high phospho-c-Met expression), 59%, 50%, and 82% (SNU-1 cell line, low phospho-c-Met expression), and 53%, 19%, and 66% in gastric fibroblasts. Immunoblot analysis of merestinib treated MKN-45 cells revealed increased expression of apoptotic proteins and decreased expression of phospho-c-Met, phospho-EGFR, phospho-IGF-1R, phospho-ERK, and phospho-AKT. In gastric fibroblasts, merestinib decreased phospho-ERK and increased apoptotic protein expression. Phospho-c-Met and phospho-EGFR were not detected in SNU-1 immunoblots; however, phospho-ERK, phospho-VEGFR, and apoptotic protein expression increased after treatment. In MKN-45 xenografts, net tumor growth in control, nab-paclitaxel, merestinib, and combination groups was 503 mm3, 115 mm3, 91 mm3, and -9.7 mm3. Immunohistochemistry analysis of tumor cell proliferation and microvessel density corroborated tumor growth study results.
 Conclusion: The data suggest that merestinib in combination with nab-paclitaxel carry a promising potential for improving clinical GAC therapy.

Efficacy and safety of lenvatinib combined with PD-1/PD-L1 inhibitors plus Gemox chemotherapy in advanced biliary tract cancer.

Lenvatinib combined with anti-PD-1 antibodies and systemic chemotherapy has demonstrated a relatively high antitumor activity for intrahepatic cholangiocarcinoma in phase 2 clinical trials. However, its efficacy and safety in advanced biliary tract cancer (BTC) has not been reported in a real-world study. Patients with advanced BTC who received lenvatinib combined with PD-1/PD-L1 inhibitors plus oxaliplatin and gemcitabine (Gemox) chemotherapy were retrospectively screened. The overall survival, progression-free survival, objective response rate, disease control rate, clinical benefit rate, and safety were evaluated. Fifty-seven patients with advanced BTC were included in the study. The median follow-up time was 15.1 (95% CI: 13.6-19.7) months. The median overall survival and progression-free survival were 13.4 (95% CI: 10.0-NA), and 9.27 (95% CI: 7.1-11.6) months, respectively. The objective response rate, disease control rate and clinical benefit rate were 43.9% (95% CI: 31.8%-56.7%), 91.2% (95% CI: 81.1%-96.2%), and 73.7% (95% CI: 61.0%-83.4%), respectively. Subgroup analysis revealed that the first-line treatment group had a longer median progression-free survival (12.13 vs. 6.77 months, P<0.01) and median overall survival (25.0 vs. 11.6 months, P=0.029) than the non-first-line treatment group. Moreover, three patients underwent conventional surgery after treatment. All patients (100%) experienced adverse events, and 45.6% (26/57) experienced grade 3 or 4 adverse events. The most commonly observed grade 3 or 4 adverse events was myelosuppression (7/57, 12.3%). No grade 5 adverse events were reported. Lenvatinib combined with PD-1/PD-L1 inhibitors and Gemox chemotherapy represents an effective and tolerable treatment option in patients with advanced BTC.

Thioparib inhibits homologous recombination repair, activates the type I IFN response, and overcomes olaparib resistance

Poly‐ADP‐ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA‐deficient tumors. However, over 40% of BRCA‐deficient patients fail to respond to PARPi. Here, we report that thioparib, a next‐generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi‐sensitive and ‐resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1‐dependent DNA damage and replication stress, causing S‐phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR‐mediated DNA repair while increasing RAD51 foci formation. Notably, the on‐target inhibition of PARP7 by thioparib‐activated STING/TBK1‐dependent phosphorylation of STAT1, triggered a strong induction of type I interferons (IFNs), and resulted in tumor growth retardation in an immunocompetent mouse model. However, the inhibitory effect of thioparib on tumor growth was more pronounced in PARP1 knockout mice, suggesting that a specific PARP7 inhibitor, rather than a pan inhibitor such as thioparib, would be more relevant for clinical applications. Finally, genome‐scale CRISPR screening identified PARP1 and MCRS1 as genes capable of modulating thioparib sensitivity. Taken together, thioparib, a next‐generation PARPi acting on both DNA damage response and antitumor immunity, serves as a therapeutic potential for treating hyperactive HR tumors, including those resistant to earlier‐generation PARPi.

Fisetin, a dietary flavonoid, increases the sensitivity of chemoresistant head and neck carcinoma cells to cisplatin possibly through HSP90AA1/IL-17 pathway.

Cisplatin (DDP) resistance is a bottleneck in the treatment of head and neck cancer (HNC), leading to poor prognosis. Fisetin, a dietary flavonoid, has low toxicity and high antitumor activity with unclear mechanisms. We intended to predict the targets of fisetin for reversing DDP-resistance and further verify their expressions and roles. A network pharmacology approach was applied to explore the target genes. The hub genes were screened out and subjected to molecular docking and experimental verification (in vivo and in vitro). Thirty-two genes common to fisetin and DDP-resistance were screened, including three hub genes, namely HSP90AA1, PPIA, and PTPRS. Molecular docking suggested that fisetin and the candidate proteins could bind tightly. HSP90AA1 was identified as the key gene. Administration of fisetin increased the sensitivity of chemoresistant cells (Cal27/DDP and FaDu/DDP) to DDP, accompanied by the downregulation of HSP90AA1 and IL-17. HSP90AA1 silencing increases the sensitivity of DDP-resistant cells to DDP, which was mediated by IL-17. In summary, fisetin might inhibit the chemoresistance of HNC cells to DDP by targeting the HSP90AA1/IL-17 pathway. Several hub genes might be the targets of fisetin for reversing DDP-resistance in HNC cells and might also serve as prognostic factors and therapeutic targets for HNC.

Bicomponent Zno-Ag janus nanoparticles with high antitumor activity &lt;I&gt;in vitro&lt;/I&gt;

Background. Nanoparticles (NPs) of zinc and silver oxide are promising antitumor agents, the use of which can enhance modern approaches to cancer treatment. Using bicomponent ZnO-Ag nanoparticles, one can increase the efficiency due to the occurrence of a synergistic antitumor effect. Among the main physicochemical properties that affect the antitumor activity of nanoparticles, one can distinguish their size and distribution of components inside the particle or their microstructure, however, these aspects are currently poorly understood.The aim of this study is the synthesis of ZnO-Ag nanoparticles using electrical explosive of wire technology and the in vitro study of the antitumor activity of NPs against breast ductal adenocarcinoma MCF-7 (ATCC HTB-22) and the HeLa cell line isolated from a cervical tumor.Material and Methods. ZnO-Ag nanoparticles were obtained by simultaneous electric explosion of zinc and silver twisted wires in a gas mixing atmosphere: argon and oxygen. The content of the components was regulated by varying the wire diameters. Physicochemical properties were studied using X-ray phase analysis, thermal desorption of nitrogen, and transmission electron microscopy. Antitumor activity in vitro was studied using the MTT test against HeLa and MCF-7 cell lines.Results. As a result of an electric explosion of twisted wires in an argon + oxygen gas mixture, ZnO-Ag NPs with different contents of components and the structure of Janus nanoparticles were obtained. The study of the physicochemical properties of nanoparticles showed that an increase in the silver content led to a decrease in the average particle size, an increase in their specific surface area, an increase in their photochemical activity and the ability to generate reactive oxygen species. The high antitumor activity of nanoparticles with a minimum silver content can be explained by a decrease in the size of silver fragments from 46 nm to 23 nm and a decrease in the average particle size from 92 nm to 54 nm. A decrease in the size of NPs and their components contributes to an increase in their solubility and, accordingly, cytotoxicity. In addition, a decrease in the size of crystallites makes it possible to increase the number and length of the ZnO-Ag interface.Conclusion. In the present study, bicomponent ZnO–Ag NPs were synthesized using the joint electric explosion of zinc and silver wires in a mixed atmosphere of argon and oxygen. A study of the physicochemical properties of nanoparticles was carried out and it was found that they all have the structure of Janus nanoparticles, an average size of 54 to 92 nm, and photochemical activity and the ability to generate ROS. Using the MTT test, the antitumor activity of NPs was confrmed using MCF-7 and HeLa cell lines. The high effciency of ZnO-Ag NPs containing 20% wt. silver indicates the possibility of using these NPs in antitumor therapy.

Maintenance therapy after allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved survival for patients with hematological malignancy, especially for those highly at risk of relapse. However, disease relapse after allo-HSCT remains the most common cause of treatment failure and death, even with conventional chemotherapy and donor lymphocyte infusion. Disease relapse in allo-HSCT can be reduced via pre-emptive treatment based on measurable residual disease and maintenance therapy for patients at high risk of relapse as promising treatment strategies. Recently, the development of novel agents and cellular therapies with high antitumor activity and less toxicity, which can be used in the post-transplant setting, has increased their clinical applications in the therapeutic approach. This review examines the current landscape and future strategies for maintenance therapy, mainly for AML and ALL after allo-HSCT.

BIOLOGICAL ACTIVITY AND PROBABLE MECHANISMS OF ACTION OF DERIVATIVES OF TRYPTANTHRIN AND MOSTOTRIN ALKALOIDS

The alkaloid tryptanthrin and its water-soluble derivative mostotrin exhibit high antimicrobial and antitumor activity. To develop more active and less toxic preparations, syntheses and testing of the biological activities of a number of new and/or little-studied analogs were performed. Some of them have been shown to have higher cytotoxicity against tumor and antimicrobial cells than tryptanthrin and mostotrin. Thus, 8-fluorotryptanthrin effectively inhibits the proliferation of various tumor cell lines, namely: K-562/4, HCT-116 and HCT-116p53ko at lower concentrations than tryptanthrin, and 2,8-difluorostotrin exhibits a stronger antimicrobial effect against pathogenic bacteria S. aureus ATCC 29213 than mostotrin. It has been established that the antiproliferative properties of 8-fluorotryptanthrin and 8-fluormostotrin are associated with their ability in nanomolar concentrations to inhibit the cell cycle of tumor cells at the stage of transition from the G1 phase to the S phase. The data obtained indicate the prospects for further in-depth studies of their antitumor properties.

Fine-tuning Bacterial Cyclic di-AMP Production for Durable Antitumor Effects Through the Activation of the STING Pathway.

The stimulator of interferon genes (STING) protein is an important and promising innate immune target for tumor therapy. However, the instability of the agonists of STING and their tendency to cause systemic immune activation is a hurdle. The STING activator, cyclic di-adenosine monophosphate (CDA), produced by the modified Escherichia coli Nissle 1917, shows high antitumor activity and effectively reduces the systemic effects of the "off-target" caused by the activation of the STING pathway. In this study, we used synthetic biological approaches to optimize the translation levels of the diadenylate cyclase that catalyzes CDA synthesis in vitro. We developed 2 engineered strains, CIBT4523 and CIBT4712, for producing high levels of CDA while keeping their concentrations within a range that did not compromise the growth. Although CIBT4712 exhibited stronger induction of the STING pathway corresponding to in vitro CDA levels, it had lower antitumor activity than CIBT4523 in an allograft tumor model, which might be related to the stability of the surviving bacteria in the tumor tissue. CIBT4523 exhibited complete tumor regression, prolonged survival of mice, and rejection of rechallenged tumors, thus, offering new possibilities for more effective tumor therapy. We showed that the appropriate production of CDA in engineered bacterial strains is essential for balancing antitumor efficacy and self-toxicity.

Synthesis, Characterization, Antimicrobial and Anticarcinogenic Activity of Quinazoline Derivatives

The reaction of β-dicarbonyl compounds as ethyl acetoacetate with hydrazines is a well-established route for the creation of pyrazole derivatives. In this research, 4-hydrazinoquinazoline (4) reacted with ethyl acetoacetate in boiling ethanol it gives ethyl 3-oxobutanoate quinazolin-4-yl-hydrazone (5). Cyclization of the compound (5) in the presence of glacial acetic acid is passed to form 4-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)quinazoline(6). Furthermore, the reaction of phenylisothiocyanate compounds with hydrazines is a well-established way for the synthesis of tetrazinoquinazoline (8). The new compounds are confirmed by elemental analysis, nuclear magnetic resonance, infrared, and mass spectra. In-vitro anti-tumor evaluation of the new compounds across three cell lines HepG2 (liver carcinoma), HCT-116 (colon carcinoma), and MCF-7 (breast carcinoma) indicats high anti-tumor activity. In addition, antimicrobial activity of specific synthesized compounds are screened against four bacterial species. Amongst four, two Gram-negative are Escherichia coli, Pseudomonas aeuroginosa and gram-positive as Staphylococcus aureus and Bacillus subtilis. The antibacterial activity of Compounds (5) and (6) are greater comparing to standard drug (Amphicillin).

The First Snake Venom KTS/Disintegrins-Integrin Interactions Using Bioinformatics Approaches.

Snake venom contains a number of active molecules that have been shown to possess high anti-tumor activities; disintegrins are an excellent example among these. Their ability to interact and bind with integrins suggests that they could be very valuable molecules for the development of new cancer therapeutic approaches. However, in the absence of a clear Lysine-Threonine-Serine (KTS) Disintegrins Integrin interaction model, the exact compound features behind it are still unknown. In this study, we investigated the structural characteristics of three KTS-disintegrins and the interaction mechanisms with the α1β1 integrin receptor using in silico bioinformatics approaches. Normal mode analysis showed that the flexibility of the KTSR motif and the C-terminal region play a key role and influence the KTS-Disintegrin-integrin interaction. Protein-protein docking also suggested that the interaction involving the KTSR motif is highly dependent on the residue following K21, S23 and R24. These findings contribute to a better understanding of the KTS-Disintegrin-Integrin structural differences and their interactions with α1β1 receptors, which could improve the selection process of the best active molecules for antitumor therapies.

Synthetic Analogs of Marine Alkaloid Aplysinopsin Suppress Anti-Apoptotic Protein BCL2 in Prostate Cancer.

Aplysinopsins are a class of indole alkaloids that possess various pharmacological activities. Although their action has been studied in regard to many diseases, their effect on prostate cancer has not yet been examined. Therefore, we synthesized a new series of aplysinopsin analogs and investigated their cytotoxic activity against prostate cancer. Five analogs showed high antitumor activity via suppressing the expression of the anti-apoptotic gene Bcl2, simulationously increasing the expression of the pro-apoptotic genes p53, Bax and Caspase 3. The inhibition of BCL2 led to the activation of BAX, which in turn activated Caspase 3, leading to apoptosis. This dual mechanism of action via apoptosis and cell cycle arrest induction is responsible for aplysinopsin analogs antitumor activity. Hence, our newly synthesized analogs are highly promising candidates for further preclinical studies against prostate cancer.

Effect of LHS-1269 on morphology and angiogenesis of Lewis lung carcinoma

Background. The new anticancer chemical compound LHS-1269 from the class of indolocarbazoles is undergoing preclinical studies at the N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia. LHS-1269 has a high antitumor activity on transplanted tumors of mice, showed high cytotoxic activity on many tumor cells lines in vitro, and has shown an inhibitory effect on vasculogenic mimicry in tumors in vitro. LHS-1269 does not affect the catalytic activity of human topoisomerases I and IIα. An antiangiogenic mechanism of the drug’s antitumor action is suggested.Aim. To evaluate the effect of LHS-1269 on the morphological features and angiogenesis of transplanted Lewis lung carcinoma (LLC) in BDF1 mice.Materials and methods. In BDF1 mice (n = 20) with transplanted LLC tumor on days 1 and 3 after 5-fold intraperitoneal administration of LHS-1269 in a single dose of 60 mg (total dose – 300 mg/kg), mice (n = 20) on days 5 and 8 after a single intravenous injection of LHS-1269 at a dose of 100 mg/kg, mice (n = 20) with transplanted LLC tumor without administration of LHS-1269 (control). The assessment of the antitumor effect was carried out according to the criterion of inhibition of tumor growth (%) and the study of the morphological features of the tumors. To assess the effect of LHS-1269 on tumor angiogenesis in LLC tumor sections, a visual calculation of the average number (density) of blood vessels and immunohistochemical detection of expression of the CD31+ endothelial marker were performed.Results. The LHS-1269 compound in animal groups with 5-fold and 1-fold use caused tumor growth inhibition – 59–70 and 67–79 %, with pronounced morphological changes and tumor cell death. There is an uneven distribution of blood vessels in tumors and surrounding tissues in all groups. LHS-1269 caused a statistically significant decrease in the average number of blood vessels in the tumor both after 5-fold and after 1-fold administration. The statistically significant decrease in the average number of blood vessels in the surrounding connective tissue tumor was observed only after 5-fold administration of the drug. The decrease in the average number of CD31+ endothelial cells after five times intraperitoneal administration was statistically insignificant compared to control (83.1 ± 8.7 and 59.6 ± 18.9, respectively). The increase in this indicator after a single intravenous injection of LHS-1269 was statistically significant.Conclusion. LHS-1269, when administered five times and once in mice, caused pronounced morphological changes in the form of damage and death of LLC tumor cells. The results of a study of angiogenesis in a tumor do not allow an unambiguous conclusion about the inhibitory effect of LHS-1269 on angiogenesis in LLC tumors in mice.

Berplatin: A Conjugate of Berberine and Cisplatin Serving as a Potent Antitumor Agent with Distinctive Tumor Cell Uptake and Minimal Side Effects

AbstractDesign of Pt(IV) prodrugs with biologically active axial ligands is an excellent approach to overcome the disadvantages (nonspecific killing, side effects, and drug resistance) of conventional first‐line Pt(II)‐based chemotherapeutic drugs, such as cisplatin, carboplatin and oxaliplatin. The selection of ideal axial ligands is essential for the success of Pt(IV) drugs. Previously, that berberine exhibits great superiority in tumor selectivity is found with uncovered mechanisms. In this study, that berberine is specifically internalized and accumulated in tumors but not normal cells through endocytosis pathways is first disclosed. Therefore a new Pt(IV) prodrug of cisplatin bearing berberine as an axial ligand, named berplatin, is designed and synthesized. Different from cisplatin, berplatin can be effectively and selectively internalized into cancer cells, through macropinocytosis and caveolin‐1 (CAV‐1)‐dependent active endocytosis, and cleaved in intracellular reductive environments to generate cisplatin and berberine, which synergistically induces substantial DNA breaking, apoptosis and cell cycle arrest in both cisplatin‐sensitive and ‐resistant cancer cells. In vivo, berplatin manifests much higher antitumor activity and undetectable side effects compared to cisplatin. This study demonstrates that berplatin can serve as a potent Pt(IV) prodrug for the treatment of cisplatin‐sensitive and ‐resistant cancers with active uptake, excellent specificity, and minimal side effects.

Efficacy of immune checkpoint inhibitors plus molecular targeted agents after the progression of lenvatinib for advanced hepatocellular carcinoma.

Lenvatinib is a standard first-line systemic therapy in advanced hepatocellular carcinoma (aHCC) and is widely used in all lines. However, the efficacy and safety of immune checkpoint inhibitors (ICIs) plus molecular targeted agents (MTAs) after the progression of lenvatinib treatment are unclear. The aim of this study was to evaluate the anticancer effects of ICI plus MTA in patients with aHCC who progressed after lenvatinib. We retrospectively included aHCC patients treated with ICI plus MTA after the progression of lenvatinib from two medical centers. Participants who continued lenvatinib treatment were classified into the "ICI+Lenva" group, while the "ICI+Others" group included patients receiving other MTAs. The efficacy endpoints were progression-free survival (PFS), post-progression survival (PPS), overall survival (OS), and tumor response following RECIST v1.1. Safety was evaluated according to Common Terminology Criteria for Adverse Events v5.0. In this study, 85 eligible aHCC patients were enrolled, including 58 in the ICI+Lenva group and 27 in the ICI+Others group. At a median follow-up time of 22.8 months, the median PPS and PFS were 14.0 (95% CI: 9.0-18.2) and 4.5 months (95% CI: 3.5-8.3), respectively. The objective response and disease control rates were 10.6% and 52.9%, respectively. No significant differences were observed in any of the efficacy endpoints between the two groups. Prolonged PPS was associated with Child-Pugh grade A, AFP < 400 IU/ml, and concomitant locoregional treatment. All patients experienced adverse events (AEs), but no fatal AEs were observed. ICI plus MTA in aHCC patients after the progression of lenvatinib presented high antitumor activity and safety. Patients could continue lenvatinib treatment and receive ICIs as well as locoregional treatment to achieve better OS.