Protein degraders are currently under rapid development as a promising modality for drug discovery. They are compounds that orchestrate interactions between a target protein and an E3 ubiquitin ligase, prompting intracellular protein degradation through proteasomal pathway. More protein degraders identification will greatly promote the development of this field. BAG3 is widely recognized as an excellent therapeutic target in cancer treatments. Exploring protein degraders that target BAG3 degradation has profound implications. Herein, molecular docking was applied to assess binding energy between 81 clinical phase I kinase inhibitors and BAG3. BAG3 protein and mRNA level were detected by western blot and quantitative real-time PCR. CCK8 assay and colony formation assay were applied to detect the cell viability and proliferation rate. Cell death was accessed using flow cytometry combined with PI and Annexin V double staining. AZD7762, a Chk1 kinase inhibitor, was identified to induce BAG3 degradation in a ubiquitin-proteasome pathway. AZD7762-induced BAG3 degradation was not dependent on Chk1 expression or activity. CRBN, an E3 ligase, was identified to bind to BAG3 and mediated BAG3 ubiquitination in the presence of AZD7762. By targeting Chk1 and BAG3, two ideal therapeutic targets in cancer treatment, AZD7762 would be a powerful chemotherapy agent in the future.

Third-generation EGFR-TKIs can be used to treat advanced non-small cell lung cancer patients with T790M resistance mutation induced by first- or second-generation EGFR-TKIs. However, it will also result in drug resistance, and the resistance mechanisms of third-generation EGFR-TKIs are complex. Here we reported a patient diagnosed with advanced lung adenocarcinoma and EGFR positive in September 2016. Following first-line targeted therapy with gefitinib, genetic testing showed EGFR T790M positive, which resulted in a change to osimertinib targeted therapy. In May 2021, troponin and creatinine levels were elevated, and the tumor hyperprogressed to severe lung cancer. Repeated genetic testing revealed that EGFR genotype converted to a non-classical mutation and EGFR T790M turned negative, which caused third-generation EGFR-TKI resistance. As a result, afatinib combined with anlotinib was selected to stabilize the patient's condition. We were inspired by the case that it reflects the significance and necessity of exploring the resistance mechanism and dynamically detecting genetic status throughout the course of treatment, which may help realize individualized precision therapy, and maximize the potential of patient.

For years, adjuvant chemotherapy has been the only standard treatment for resected non-small cell lung cancer patients (NSCLC), offering a dismal survival improvement at 5 years. Following the outstanding results of the recent ADAURA trial, osimertinib has become a new standard treatment for resected epidermal growth factor receptor (EGFR)-mutant non-squamous NSCLC, regardless of the administration of chemotherapy. For patients whose disease relapses after completion of the adjuvant therapy, there is no consensus about the optimal treatment. Herein, we report the case of a 74-year-old woman diagnosed with stage IIIA non-squamous NSCLC, harboring the EGFR p.L858R mutation. After complete tumor resection, the patient received adjuvant chemotherapy with cisplatin and vinorelbine, followed by osimertinib 80 mg daily for 3 years within the ADAURA trial. Brain disease relapse was documented 18 months after treatment completion by computed tomography scans. The patient was then retreated with osimertinib obtaining a deep intracranial partial response, which is still lasting after 21 months. The retreatment with osimertinib in patients whose disease relapsed following adjuvant therapy with the third-generation EGFR inhibitor might be a valid option, especially in patients with intracranial disease relapse. Studies are warranted to confirm this finding and to define the impact of the disease-free interval in this regard.

Prostate cancer (PCa) has become the major health problem and the leading causes of cancer mortality among men. PCa often progresses from an early androgen-dependent form of cancer to a late (metastatic) androgen-independent cancer, for which no effective treatment options are available. Current therapies target testosterone depletion, androgen axis inhibition, androgen receptor (AR) downregulation and regulation PSA expression. These conventional treatment options, however, are intense and pose severe side effects. From the past few years, plant-derived compounds or phytochemicals have attracted much attention by the researchers worldwide for their promising approach in inhibiting the development and growth of cancer. This review emphasizes mechanistic role of promising phytochemicals on PCa. This review imparts to score anticancer efficacy of promising phyto-agents luteolin, fisetin, coumestrol and hesperidin with focus on the mechanistic action in management and treatment of PCa. These phytocompounds were also selected for their best binding affinity with the ARs on the basis of molecular docking studies.

Nasopharyngeal carcinoma (NPC) is a malignant tumor caused by nasopharyngeal epithelium. Long non-coding RNAs (lncRNAs) and microRNAs have been identified as vital regulators in many tumors, including NPC. This study aimed to explain the biological roles and relevant mechanisms of lncRNA FOXP4-AS1 (FOXP4-AS1) in NPC. The levels of lncRNA FOXP4-AS1, miR-136-5p and MAPK1 in C666-1 and NP69 cells were analyzed by quantitative reverse transcription PCR (qRT-PCR). C666-1 cells viability, migration and invasion were evaluated by MTT and Transwell assay, respectively. The target gene of miR-136-5p predicted by TargetScan was further verified using dual luciferase reporter assay. Moreover, qRT-PCR and Western blot were adopted to assess epithelial–mesenchymal transition (EMT)-related gene expression, including E-cadherin and N-cadherin. We found that lncRNA FOXP4-AS1 was upregulated, while miR-136-5p was low-expressed in C666-1 cells, as opposed to NP69. Knockdown of FOXP4-AS1 notably suppressed C666-1 cell growth, inhibited cell migration and invasion. We also observed that E-cadherin expression was fortified and N-cadherin level was decreased in C666-1 cells after FOXP4-AS1-siRNA transfection. However, all these findings were eliminated in C666-1 cells after miR-136-5p inhibitor treatment. We also found miR-136-5p directly targeted MAPK1 and correlated inversely with MAPK1 expression in C666-1 cells. Further investigation suggested that MAPK1-plasmid reversed the effects of miR-136-5p mimic on cells viability, migration, invasion and EMT. To conclude, our data revealed that lncRNA FOXP4-AS1 knockdown alleviated metastasis and EMT in NPC via miR-136-5p/MAPK1, indicating that lncRNA FOXP4-AS1 may be a valuable therapeutic target for NPC diagnosis and treatment.

Colorectal cancer is one of the most common types of cancer in the world and the study of the role of nutrients in preventing or inhibiting the growth of this cancer is of interest to scientists. In this article, the synergistic effect of deuterium-depleted water(DDW) and crocin at specific concentrations on HT-29 cells was investigated. In this regard, HT-29 cells were grown in RPMI medium containing DDW, alone and in combination with crocin for 24, 48 and 72 h. Cell viability, cell cycle changes and antioxidant enzymes status were determined by MTT assay, flow cytometry and quantitative luminescence methods, respectively. The results of these analyses proved the cell growth inhibitory effect of deuterium alone and its synergistic effect in combination with crocin. The cell cycle analysis showed an increase in the number of cells in the G0 and G1 phases whereas there was a decrease in the number of cells in the S, G2 and M phases. The activities of superoxide dismutase and catalase enzymes also decreased compared to the control group that is a reason to increase Malonyl dialdehyde factor. The results suggested that a combination of DDW and crocin can open a new strategic approach in the prevention and treatment of colorectal cancer.

Enhancing research indicatedthat circular RNA (circRNA) acted a critical part in cholangiocarcinoma (CHOL) development. This research aims to discover the role of circRNA SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 5 (SMARCA5) in CHOL bio-progression, which has been proved to be downregulated in CHOL tissues. In this study, quantitative reverse transcription polymerase chain reaction was used to reveal the level and linkage of circRNA SMARCA5, miRNA-95-3p and TNF receptor-associated factor 3 gene (TRAF3) in CHOL tissues and cancer cells. The target sites of circRNA SMARCA5 and miRNA-95-3p were forecast by Starbase, and Targetscan was conducted to forecast the potential linkage points of TRAF3 and miRNA-95-3p, and which is affirmed by double luciferase reporter assay. CCK-8 and flow cytometry assay was carried to indicate cell viability. And apoptosis-related protein was counted by caspase3 activity and Western blot assay. CircRNA SMARCA5 was downregulated in CHOL cell lines and cancer samples. Besides, over-expression of SMARCA5 inhibited cell growth and promoted apoptotic rate. Dual-luciferase reporter assays presented that miRNA-95-3p could link with circRNA SMARCA5. Moreover, miRNA-95-3p was discovered highly expressed in CHOL. Interference of miRNA-95-3p repressed cell proliferation and raised the apoptosis. Importantly, TRAF3 was validated to be a downstream of miRNA-95-3p. Strengthen of miRNA-95-3p reversed the inhibitory impact of circRNA SMARCA5-plasmid transfection, and the results of miRNA-95-3p inhibitor were reversed by si-TRAF3. CircRNA SMARCA5 is involved in CHOL development by interosculating miRNA-95-3p/TRAF3 axis and may become a novel approach for treating CHOL.

In view of the success of targeted therapy in the field of advanced lung cancer, it is gradually pushed further to neoadjuvant therapy. Alectinib has been recommended for advanced anaplastic lymphoma kinase (ALK) + non-small cell lung cancer (NSCLC) in first-line therapy. Here, we report two cases of neoadjuvant alectinib in locally advanced lung adenocarcinoma with ALK rearrangement. Case 1 was a 64-year-old man with no history of smoking who was diagnosed with the clinical stage as IIIB, with ALK fusion-positive. Chest-enhanced computed tomography (CT) revealed marked regression and achieved partial response (PR) incorporated with grade 3 interstitial pneumonia after 44 days of alectinib neoadjuvant therapy. Interstitial pneumonia improved after methylprednisolone therapy, then thoracoscopic lobe resection with lymph node dissection was performed with blood loss. The pathological assessment was a pathologic complete response(pCR). Case 2 was a 66-year-old man who had a routine physical examination and then diagnosed with a clinical-stage IIIB by CT-guided percutaneous cutting needle biopsy (PCNB). Chemotherapy with 1 cycle of pemetrexed combined with nedaplatin was performed in the interval waiting for next-generation sequencing (NGS) results. NGS testing revealed an EML4-ALK fusion mutation. After 109 days of alectinib treatment, radiographic evaluation was classified as PR and then he underwent thoracoscopic upper lobectomy smoothly with pathological assessment as a major pathological response (MPR). To date, neoadjuvant alectinib has only been reported in a few cases in locally advanced lung adenocarcinoma with ALK-rearranged. Neoadjuvant alectinib may be feasible in locally advanced disease for complete resection. The duration and safety of neoadjuvant therapy with alectinib still need further study.

Cisplatin (DDP) was a commonly used drug in the treatment of nonsmall cell lung cancer (NSCLC). However, the current resistance of patients to DDP seriously affected its therapeutic effect. Circular RNAs (circRNAs) have been reported to regulate drug resistance in cells. The purpose of this paper is to study the effect of circRNA B cell linker (circ_BLNK) in DDP resistance of NSCLC. The abundances of circ_BLNK, microRNA-25-3p (miR-25-3p) and BarH‑like homeobox 2 (BARX2) were examined by quantitative real-time PCR and western blot analysis. Cell proliferation and apoptosis were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, EdU assay and flow cytometry. Transwell assay was applied to assess cell migration and invasion. Protein levels were quantified by western blot analysis. Dual-luciferase reporter assay was enforced to confirm the links among circ_BLNK, miR-25-3p and BARX2. The mice models were enforced to evaluate tumorigenicity. Herein, circ_BLNK and BARX2 were lower-expressed, whereas miR-25-3p was higher-expressed in A549/DDP and H1299/DDP cells than their homologous parental NSCLC cells. Circ_BLNK increases improved DDP sensitivity of NSCLC cells by promoting cell apoptosis and inhibiting proliferation, migration and invasion. Moreover, we confirmed that circ_BLNK regulated BARX2 by inhibiting miR-25-3p. Accordingly, overexpression of circ_BLNK improved DDP sensitivity of NSCLC cells via miR-25-3p/BARX2 axis. Besides, circ_BLNK reduced cell resistance to DDP, thereby inhibiting tumor development in mice. Circ_BLNK promoted the DDP sensitivity of NSCLC via regulating miR-25-3p/BARX2 axis.

Anlotinib has been approved as the third-line or beyond treatment regimen for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, it is indistinct whether there are survival benefits of anlotinib in the maintenance therapy of ES-SCLC. Therefore, this study aims to evaluate the efficacy and safety of anlotinib monotherapy as maintenance therapy after induction chemotherapy for patients with ES-SCLC. The median progression-free survival (mPFS) was considered to be the pivotal symbol as the primary endpoint. The median overall survival (mOS) and safety were recognized as the second endpoints. Eligible patients in stable status after first-line chemotherapy would subsequently accept oral anlotinib (12 mg/d, d1-d14, every 21 days as a course). The maintenance method was continued until disease progression or unmanageable toxicity occurred. The mPFS was 7.7 months (95% CI, 7.20-8.20 months) and the mOS was 11.0 months (95% CI, 9.19-12.82 months), respectively. The most common treatment-related adverse events were hypertension ( n = 9; 64.3%), fatigue ( n = 6; 42.9%), followed by decreased appetite ( n = 5; 35.7%), nausea ( n = 5; 35.7%), weight decrease ( n = 4; 28.6%), and rash ( n = 4; 28.6%). There were no patients who required dose reduction because of severe adverse events. Anlotinib achieved prospective efficacy and manageable safety in the maintenance treatment of ES-SCLC. These above outcomes demonstrated that anlotinib was a tolerable and potent maintenance treatment option after induction chemotherapy in ES-SCLC.