EGFR and VEGFR-2 represent promising targets for cancer treatment as they are very important in tumor development as well as in angiogenesis and metastasis. In this work, 6-amino-4-(2-bromophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 1 and (E)-4-(2-Bromobenzylidene)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 11 were selected as starting materials to synthesize different fused pyrazole derivatives; dihydropyrano[2,3-c]pyrazole 1, 2, 7-9, and 15, pyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidine 3-6, pyrazolo[3,4-d]pyrimidine 12 and 13, and pyrazolo[3,4-c]pyrazole 14 derivatives were synthesized to evaluate their anticancer activity against HEPG2 human cancer cell lines compared to erlotinib and sorafenib as reference drugs. Seven compounds 1, 2, 4, 8, 11, 12, and 15 showed nearly 10 fold higher activity than erlotinib (10.6 μM) with IC50 ranging from 0.31 to 0.71 μM. In vitro EGFR and VEGFR-2 inhibitory activity were performed for the synthesized compounds, and the results identified compound 3 as the most potent EGFR inhibitor (IC50 = 0.06 μM) and compound 9 as the most potent VEGFR-2 inhibitor (IC50 = 0.22 μM). Moreover, compounds 9 and 12 revealed potent dual EGFR and VEGFR-2 inhibition, and these results were supported by docking studies of these two compounds within the active sites of both enzymes.

/pdf/novel-anticancer-fused-pyrazole-derivatives-as-egfr-and-1c81qrzwb0.pdf

Novel Anticancer Fused Pyrazole Derivatives as EGFR and VEGFR-2 Dual TK Inhibitors.

Background Recently, a variety of clinical trials have shown that apatinib, a small-molecule anti-angiogenic drug, exerts promising inhibitory effects on multiple solid tumors, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism of apatinib on NSCLC remains unclear. Methods MTT, EdU, AO/EB staining, TUNEL staining, flow cytometry, colony formation assays were performed to investigate the effects of apatinib on cell proliferation, cell cycle distribution, apoptosis and cancer stem like properties. Wound healing and transwell assays were conducted to explore the role of apatinib on migration and invasion. The regulation of apatinib on VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling were detected. Furthermore, we collected conditioned medium (CM) from A549 and H1299 cells to stimulate phorbol myristate acetate (PMA)-activated THP-1 cells, and examined the effect of apatinib on PD-L1 expression in macrophages. The Jurkat T cells and NSCLC cells co-culture model was used to assess the effect of apatinib on T cells activation. Subcutaneous tumor formation models were established to evaluate the effects of apatinib in vivo. Histochemical, immunohistochemical staining and ELISA assay were used to examine the levels of signaling molecules in tumors. Results We showed that apatinib inhibited cell proliferation and promoted apoptosis in NSCLC cells in vitro. Apatinib induced cell cycle arrest at G1 phase and suppressed the expression of Cyclin D1 and CDK4. Moreover, apatinib upregulated Cleaved Caspase 3, Cleaved Caspase 9 and Bax, and downregulated Bcl-2 in NSCLC cells. The colony formation ability and the number of CD133 positive cells were significantly decreased by apatinib, suggesting that apatinib inhibited the malignant and stem-like features of NSCLC cells. Mechanistically, apatinib inhibited PD-L1 and c-Myc expression by targeting VEGFR2/STAT3 signaling. Apatinib also inhibited PD-L1 expression in THP-1 derived macrophages stimulated by CM from NSCLC cells. Furthermore, apatinib pretreatment increased CD69 expression and IFN-γ secretion in stimulated Jurkat T cells co-cultured with NSCLC cells. Apatinib also promoted ROS production and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Moreover, apatinib significantly inhibited tumor growth in vivo. Conclusion Our data indicated that apatinib induced autophagy and apoptosis in NSCLC via regulating VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling.

/pdf/apatinib-triggers-autophagic-and-apoptotic-cell-death-via-2max9sh6w8.pdf

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer.

Bone and soft tissue sarcomas are rare malignant tumors originated from mesenchymal tissues. They harbor more than 50 distinct subtypes and differ in pathological features and clinical courses. Despite the significant improvements in modern multi-modality treatment, the outcomes and overall survival rates remain poor for patients with advanced, refractory, metastatic, or relapsed diseases. The growth and metastasis of bone and soft tissue sarcoma largely depend on angiogenesis, and VEGF/VEGFR pathway is considered as the most prominent player in angiogenesis. Therefore, blockade of VEGF/VEGFR pathways is a promising therapeutic strategy to retard neovascularization. Several VEGFR inhibitors have been developed and revealed their favorable anti-neoplastic effects in various cancers, but such desirable anti-tumor effects are not obtained in advanced sarcomas because of multiple reasons, such as drug tolerance, short duration of response, and severe adverse effects. Fortunately, preclinical and clinical studies have indicated that apatinib is a novel promising VEGFR2 inhibitor showing potent anti-angiogenic and anti-neoplastic activities in advanced sarcomas. Especially, apatinib has showed notable characteristics in multidrug resistance reversal, tumor regression, vascular normalization, immunosuppression alleviation, and enhancement of chemotherapeutic and radiotherapeutic effects. However, apatinib also gets struck in dilemma of reversing multidrug resistance of chemotherapeutic agents while suffering drug resistance itself, and several difficulties should be tackled before full use of apatinib. In this review, we discuss the outstanding characteristics and main predicaments of apatinib as targeted therapy in advanced sarcomas. Bone and soft tissue sarcomas are rare but malignant tumors originated from mesenchymal tissues. They harbor more than 100 distinct subtypes and differ in features of pathologies and clinical courses. Despite the significant improvements in modern multi-modality treatment, the outcomes and overall survival rates remain poor for patients with advanced, refractory, metastatic, or relapsed lesions. The growth and metastasis of bone and soft tissue sarcoma largely depend on angiogenesis and VEGF/VEGFR pathways play a pivotal role in angiogenesis. Therefore, blockade of VEGF/VEGFR pathways is a promising therapeutic strategy. Several VEGFR inhibitors have been developed and verified in clinical trials but with unfavorable outcomes. Fortunately, preclinical studies and clinical trials have indicated that apatinib is a novel promising VEGFR2 inhibitor showing potent anti-angiogenic and anti-neoplastic activities in advanced sarcomas. Actually, apatinib has showed notable characteristics in multidrug resistance reversal, tumor regression, vascular normalization, immunosuppression alleviation, enhancement of chemotherapeutic and radiotherapeutic effects. However, apatinib also gets struck in dilemma of reversing multidrug resistance of chemotherapeutic agents while suffering drug resistance itself, and several difficulties should be tackled before full use of apatinib. In this review, we discuss the outstanding characteristics and main predicaments of apatinib as targeted therapy in advanced sarcomas.

Apatinib as targeted therapy for advanced bone and soft tissue sarcoma: a dilemma of reversing multidrug resistance while suffering drug resistance itself

BACKGROUND This study aimed to investigate the role of miRNA-339-5p in pancreatic cancer cell invasion and migration. MATERIAL AND METHODS The differences between exosomal miRNAs of PANC02 and PANC02-H7 were studied by microarray analysis. We measured miRNA-339-5p expression in different groups; differences in cell invasion and migration were evaluated using the Transwell and wound healing assays and expression of relative proteins (E-cadherin, vimentin and ZNF689) was measured by WB assay. The correlation between miRNA-339-5p and ZNF689 expression was evaluated by luciferase reporter gene assay. RESULTS Compared with PANC02 exosome, microarray analysis indicated that miRNA-339-5p mRNA expression was significantly suppressed (P<0.001) in the PANC02-H7 exosome. Supplementation with miR-339-5p mimics led to a significant decrease in the invasion cell number and wound healing rate (P<0.001), with significantly enhanced E-cadherin expression and suppressed vimentin expression (P<0.001). However, transfection of a miR-339-5p inhibitor led to a significant increase in the invasion cell number and wound healing rate (P<0.001), with significantly suppressed E-cadherin expression and increased vimentin expression (P<0.001). Luciferase reporter gene assay demonstrated ZNF689 gene to be the target of miR-339-5p in the PANC02-H7 cell. With miR-339-5p and ZNF689 transfection, the invasion cell number and wound healing rate were significantly increased compared with those in the miR-339-5p group (P<0.001), with significantly increased expression of ZNF689 and vimentin and suppressed E-cadherin expression (P<0.001). CONCLUSIONS miR-339-5p suppresses the invasion and migration of pancreatic cancer cells via direct regulation of ZNF689 in vitro.

/pdf/mirna-339-5p-plays-an-important-role-in-invasion-and-2ptzrcccrl.pdf

miRNA-339-5p Plays an Important Role in Invasion and Migration of Pancreatic Cancer Cells

Liver cancer is the 7th utmost frequent neoplasm and the 4th principal source of cancer deaths This malignancy is linked with several environmental and lifestyle-related factors emphasizing the role of epigenetics in its pathogenesis MicroRNAs (miRNAs) have been regarded as potent epigenetic mechanisms partaking in the pathogenesis of liver cancer Dysregulation of miRNAs has been related with poor outcome of patients with liver cancer In the current manuscript, we provide a concise review of the results of recent studies about the role of miRNAs in the progression of liver cancer and their diagnostic and prognostic utility

MicroRNA signature in liver cancer.

Liver cancer is the third most common cause of cancer related death worldwide. Apatinib showed satisfactory efficacy in various types of cancers, including breast cancer, malignant fibrous histiocytoma and liver cancer. However, how did Apatinib function in liver cancer is largely unknown. mRNA levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) as well as protein levels of VEGF and p-VEGFR2 were obviously higher in liver cancer cell line SMCC7721 than in normal liver cell LO2. Apatinib significantly inhibited the mRNA levels of VEGF and VEGFR2 as well as protein levels of VEGF and p-VEGFR2 compared with those in control group. At 12, 24 and 48 h after corresponding treatments, compared with the control group, Apatinib significantly lowered the cell viability of SMCC7721 cells, while transfection of si-signal transducer and activator of transcription 3 (siSTAT3) further augmented the effects of Apatinib. At 48 h after treatment, compared with the control group, Apatinib significantly upregulated the cell apoptosis rate of SMCC7721 cells, which was further induced by the transfection of siSTAT3. Compared with control group, Apatinib significantly induced BAX/Bcl-2 ratio elevation, reduced p-STAT3 and p-VEGFR2 expression, which were significantly augmented by the treatment of siSTAT3. In conclusion, Apatinib inhibited the cell proliferation and promoted the cell apoptosis of liver cancer by inhibiting the activation of VEGFR2/STAT3.

Apatinib regulates the cell proliferation and apoptosis of liver cancer by regulation of VEGFR2/STAT3 signaling

Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide, however, the prognosis for HCC remains unsatisfactory. This study aimed to explore the role of miR-339-5p in HCC. Methods We first used quantitative real-time PCR to examine the level of miR-339-5p in HCC tissues. Then we further adopted Western blotting assay, CCK8, cell invasion assays, apoptosis detection assay, and luciferase assay to analyze how it mediate the development of HCC. Results We found that miR-339 is significantly decreased in primary HCC tissues. Overexpression of miR-339 in HCC cells remarkably suppressed proliferation and invasion and induced apoptosis. However, silencing miR-339 in HCC cells promoted proliferation and invasion, and reduced apoptosis. Moreover, we demonstrated that ZNF689 is a target of miR-339 and there is a negative correlation between miR-339 and ZNF689 expression in the HCC tissues. Overexpression of ZNF689 in miR-339-overexpressing HCC cells partially antagonized the inhibitory effects of miR-339. Conclusion Our study revealed that miR-339 inhibits HCC growth through targeting oncoprotein ZNF689 and restoration of miR-339 might be feasible therapeutic strategy for HCC treatment.

/pdf/microrna-339-inhibits-human-hepatocellular-carcinoma-2dofset3ss.pdf

MicroRNA-339 inhibits human hepatocellular carcinoma proliferation and invasion via targeting ZNF689.

Introduction Immune checkpoint inhibition (ICI) plus bevacizumab (BEV) is the standard first-line treatment for unresectable hepatocellular carcinoma (uHCC). We aimed to assess the efficacy and safety of ICI plus bevacizumab and ICI plus receptor tyrosine kinase inhibitor (TKI) in this patient population. Methods This retrospective single-institution study enrolled 94 patients with uHCC who received ICI plus TKI or bevacizumab as the first-line treatment. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were used to evaluate treatment efficacy. RECIST v1.1 criteria were used to calculate the objective clinical response. Common Terminology Criteria for Adverse Events were used to report and categorize adverse events. Results By the last follow-up interview on May 15, 2022, there were 57 deaths, and 19 patients did not develop disease progression. Thirty patients received sintilimab/atezolizumab plus bevacizumab (ICI + BEV group), and 64 received ICI plus TKI (ICI + TKI group). The median OS was 430 days (95% CI, 266-NA) in the ICI+TKI group and 498 days (95% CI, 349-NA) in the ICI+BEV group (HR, 1.20; 95% CI, 0.69-2.07; P = 0.52). There was no significant difference between the two groups in the median PFS (182 vs. 221 days, P=0.67). In the ICI+TKI group, the ORR and DCR were 28.1% and 67.2%, respectively. In the ICI+BEV group, the ORR and DCR were 26.7% and 66.7%, respectively. The overall incidence of adverse events was similar between the two groups. Palmar-plantar erythrodysesthesia syndrome (23[36%]) occurred only in the ICI + TKI group. Patients who received ICI+BEV were more prone to upper gastrointestinal bleeding (2 [7%]), with one patient with grade 4 requiring emergency DSA treatment. Conclusion This study found that ICI+TKI and ICI+BEV as first-line treatments were similar in OS, PFS, and tumor response in uHCC. Different populations are suitable for different regimens because of the different adverse events.

/pdf/the-effect-of-anti-pd-1-pd-l1-antibodies-combined-with-vegf-2c9y3uby.pdf

The effect of anti-PD-1/PD-L1 antibodies combined with VEGF receptor tyrosine kinase inhibitors versus bevacizumab in unresectable hepatocellular carcinoma

BACKGROUND
Many patients with cholangiocarcinoma also present with malignant obstructive jaundice (MOJ), which requires biliary drainage and stent placement. Recently, clinicians have tried to implant iodine-125 seeds into the biliary tract. However, we know very little about this treatment. This study aimed to compare biliary stenting alone and stenting combined with iodine-125 seed strand implantation to evaluate the safety and efficacy of this technique.


METHODS
Sixty patients of cholangiocarcinoma with MOJ were enrolled into the study. According to voluntary choices, 30 received biliary stenting combined with iodine-125 seed strand implantation (study group), and 30 received biliary stent implantation alone (control group). Various biochemical indicators and the manifestation of computed tomography (CT) or magnetic resonance imaging (MRI) were compared before and after operation. We evaluated the safety and efficacy of these treatments by observing patients' symptoms, biochemical indicators and imaging data. Individualized antitumor therapy and regular follow-up were given according to the patients' condition.


RESULTS
All 60 patients successfully completed operation. There were no statistically significant differences in baseline data between two groups (P>0.05). Before and 4 weeks after operation, the average total bilirubin levels decreased from 268.14±114.97 to 54.00±80.78 µmol/L in study group, and decreased from 228.89±162.04 to 58.80±61.14 µmol/L in control group. The difference between two groups was not statistically significant (P=0.796). Before and 4 weeks after operation, the average Child-Pugh scores decreased from 7.83±0.59 to 6.20±1.03 points in study group, and decreased from 7.93±1.08 to 7.07±1.39 points in control group, with a statistically significant difference between two groups (P=0.008). The median patency time of stents was 41.71±3.46 weeks in study group and 29.00±5.81 weeks in control group, with a statistically significant difference between the two groups (P=0.037). A statistically significant difference in disease control rate (DCR) was observed between the two groups (P=0.045).


CONCLUSIONS
This study demonstrated biliary stenting combined with iodine-125 seed strand implantation may be consider as a safe treatment option for the patients of cholangiocarcinoma with MOJ, and this treatment may improve liver function, reduce the incidence of in-stent restenosis, and improve DCR.

/pdf/the-efficacy-and-safety-of-biliary-stenting-alone-versus-3ucur7aj.pdf

The efficacy and safety of biliary stenting alone versus stenting combined with iodine-125 seed strand implantation for the treatment of cholangiocarcinoma with malignant obstructive jaundice: a prospective, nonrandomized, controlled clinical study.

Objective Thermal ablation is a minimally invasive procedure for the treatment of pulmonary malignancy, but the intraoperative measure of complete ablation of the tumor is mainly based on the subjective judgment of clinicians without quantitative criteria. This study aimed to develop and validate an intraoperative computed tomography (CT)-based radiomic nomogram to predict complete ablation of pulmonary malignancy. Methods This study enrolled 104 individual lesions from 92 patients with primary or metastatic pulmonary malignancies, which were randomly divided into training cohort (n=74) and verification cohort (n=30). Radiomics features were extracted from the original CT images when the study clinicians determined the completion of the ablation surgery. Minimum redundancy maximum relevance (mRMR) and least absolute shrinkage and selection operator (LASSO) were adopted for the dimensionality reduction of high-dimensional data and feature selection. The prediction model was developed based on the radiomics signature combined with the independent clinical predictors by multiple logistic regression analysis. The area under the curve (AUC), accuracy, sensitivity, and specificity were calculated. Receiver operating characteristic (ROC) curves and calibration curves were used to evaluate the predictive performance of the model. Decision curve analysis (DCA) was applied to estimate the clinical usefulness and net benefit of the nomogram for decision making. Results Thirteen CT features were selected to construct radiomics prediction model, which exhibits good predictive performance for determination of complete ablation of pulmonary malignancy. The AUCs of a CT-based radiomics nomogram that integrated the radiomics signature and the clinical predictors were 0.88 (95% CI 0.80-0.96) in the training cohort and 0.87 (95% CI: 0.71–1.00) in the validation cohort, respectively. The radiomics nomogram was well calibrated in both the training and validation cohorts, and it was highly consistent with complete tumor ablation. DCA indicated that the nomogram was clinically useful. Conclusion A CT-based radiomics nomogram has good predictive value for determination of complete ablation of pulmonary malignancy intraoperatively, which can assist in decision-making.

Jun Luo

Papers

Apatinib regulates the cell proliferation and apoptosis of liver cancer by regulation of VEGFR2/STAT3 signaling

MicroRNA-339 inhibits human hepatocellular carcinoma proliferation and invasion via targeting ZNF689.

The effect of anti-PD-1/PD-L1 antibodies combined with VEGF receptor tyrosine kinase inhibitors versus bevacizumab in unresectable hepatocellular carcinoma

The efficacy and safety of biliary stenting alone versus stenting combined with iodine-125 seed strand implantation for the treatment of cholangiocarcinoma with malignant obstructive jaundice: a prospective, nonrandomized, controlled clinical study.

A CT-Based Radiomics Nomogram to Predict Complete Ablation of Pulmonary Malignancy: A Multicenter Study