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Chronic myeloid leukemia (CML), a myeloproliferative hematopoietic cancer, is caused by a genetic translocation between chromosomes 9 and 22. This translocation produces a small Philadelphia chromosome, which contains the Bcr-Abl oncogene. The Bcr-Abl oncogene encodes the BCR-ABL protein, upregulates various signaling pathways (JAK-STAT, MAPK/ERK, and PI3K/Akt/mTOR), and out of which the specifically highly active pathway is the PI3K/Akt/mTOR pathway. Among early treatments for CML, tyrosine kinase inhibitors (TKIs) were found to be the most effective, but drug resistance against kinase inhibitors led to the discovery of novel alternative therapies. At this point, the PI3K/Akt/mTOR pathway components became new targets due to stimulation of this pathway in TKIs-resistant CML patients. The current review article deals with reviewing the scientific literature on the PI3K/Akt/mTOR pathway inhibitors listed in the National Cancer Institute (NCI) drug dictionary and proved effective against multiple cancers. And out of those enlisted inhibitors, the US FDA has also approved some PI3K inhibitors (Idelalisib, Copanlisib, and Duvelisib) and mTOR inhibitors (Everolimus, Sirolimus, and Temsirolimus) for cancer therapy. So far, several inhibitors have been tested, and further investigations are still ongoing. Even in Imatinib, Nilotinib, and Ponatinib-resistant CML cells, a dual PI3K/mTOR inhibitor, BEZ235, showed antiproliferative activity. Therefore, by considering the literature data of these reviews and further examining some of the reported inhibitors, which proved effective against the PI3K/Akt/mTOR signaling pathway in multiple cancers, may improve the therapeutic approaches towards TKI-resistant CML cells where the respective signaling pathway gets upregulated.

The PI3K-AKT-mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective inhibitor alpelisib (BYL719), currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited), nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described.

Nobiletin (NOB) is a polymethoxylated flavonoid isolated from citrus fruit peel that has been shown to possess anti-tumor, antithrombotic, antifungal, anti-inflammatory and anti-atherosclerotic activities. The main purpose of this study was to explore the potential of using NOB to induce apoptosis in human bladder cancer cells and study the underlying mechanism. Using an MTT assay, agarose gel electrophoresis, a wound-healing assay, flow cytometry, and western blot analysis, this study investigated the signaling pathways involved in NOB-induced apoptosis in BFTC human bladder cancer cells. Our results showed that NOB at concentrations of 60, 80, and 100 μM inhibited cell growth by 42%, 62%, and 80%, respectively. Cells treated with 60 μM NOB demonstrated increased DNA fragmentation, and flow cytometry analysis confirmed that the treatment caused late apoptotic cell death. Western blot analysis showed that mitochondrial dysfunction occurred in NOB-treated BFTC cells, leading to cytochrome C release into cytosol, activation of pro-apoptotic proteins (caspase-3, caspase-9, Bad, and Bax), and inhibition of anti-apoptotic proteins (Mcl-1, Bcl-xl, and Bcl-2). NOB-induced apoptosis was also mediated by regulating endoplasmic reticulum stress via the PERK/elF2α/ATF4/CHOP pathway, and downregulating the PI3K/AKT/mTOR pathway. Our results suggested that the cytotoxic and apoptotic effects of NOB on bladder cancer cells are associated with endoplasmic reticulum stress and mitochondrial dysfunction.

Proteasome 26S subunit ATPase 4 (PSMC4) could regulate cancer progression. However, the function of PSMC4 in prostate carcinoma (PCa) progression requires further clarification. In the study, PSMC4 and chromobox 3 (CBX3) levels were verified by TCGA data and tissue microarrays. Cell counting kit‐8, cell apoptosis, cell cycle, wound healing, transwell and xenograft tumour model assays were performed to verify biological functions of PSMC4 in PCa. RNA‐seq, PCR, western blotting and co‐IP assays were performed to verify the mechanism of PSMC4. Results showed that PSMC4 level was significantly increased in PCa tissues, and patients with PCa with a high PSMC4 level exhibited shorter overall survival. PSMC4 knockdown markedly inhibited cell proliferation, cell cycle and migration in vitro and in vivo, and significantly promoted cell apoptosis. Then further study revealed that CBX3 was a downstream target of PSMC4. PSMC4 knockdown markedly reduced CBX3 level, and inhibited PI3K‐AKT‐mTOR signalling. CBX3 overexpression markedly promoted epidermal growth factor receptor (EGFR) level. Finally, PSMC4 overexpression showed reverse effect in DU145 cells, and the effects of PSMC4 overexpression on cell proliferation, migration and clonal formation were rescued by the CBX3 knockdown, and regulated EGFR‐PI3K‐AKT‐mTOR signalling. In conclusion, PSMC4 could regulate the PCa progression by mediating the CBX3‐EGFR‐PI3K‐AKT‐mTOR pathway. These findings provided a new target for PCa treatment.

Objectives The purpose of this study was to investigate the treatment effect and molecular mechanism of tetrahedral framework nucleic acids (tFNAs), novel self‐assembled nucleic acid nanomaterials, in diffuse BMEC injury after SAH. Materials and Methods tFNAs were synthesized from four ssDNAs. The effects of tFNAs on SAH‐induced diffuse BMEC injury were explored by a cytotoxicity model induced by hemin, a breakdown product of hemoglobin, in vitro and a mouse model of SAH via internal carotid artery puncture in vivo. Cell viability assays, wound healing assays, transwell assays, and tube formation assays were performed to explore cellular function like angiogenesis. Results In vitro cellular function assays demonstrated that tFNAs could alleviate hemin‐induced injury, promote angiogenesis, and inhibit apoptosis in hemin cytotoxicity model. In vivo study using H&E and TEM results jointly indicated that the tFNAs attenuate the damage caused by SAH in situ, showing restored number of BMECs in the endothelium layer and more tight intercellular connectivity. Histological examination of SAH model animals confirmed the results of the in vitro study, as tFNAs exhibited treatment effects against diffuse BMEC injury in the cerebral microvascular bed. Conclusions Our study suggests the potential of tFNAs in ameliorating diffuse injury to BMECs after SAH, which laid theoretical foundation for the further study and use of these nucleic acid nanomaterials for tissue engineering vascularization. The potential of tFNAs in ameliorating diffuse injury to BMECs after SAH, laying a theoretical foundation for the further study and the use of these nucleic acid nanomaterials.

Background: Chronic atrophic gastritis precancerous lesions (PL-CAG) are characterized by the atrophy of gastric mucosal glands, often accompanied by intestinal metaplasia or dysplasia. Timely intervention and treatment can effectively reverse its malignant progression and prevent the onset of gastric cancer. Bombyx Batryticatus (BB) exhibits a range of pharmacological effects, including anticoagulation, antiepileptic properties, anticancer activity, and antibacterial effects. However, the pharmacological basis and mechanisms underlying BB’s efficacy in treating PL-CAG remain unclear. Methods: A three-factor modeling approach was implemented to develop a rat PL-CAG model, while the MNNG-induced PLGC (precancerous lesions of gastric cancer) cell model was served as a cell PL-CAG model. UPLC-QE-Orbitrap-MS/MS (Ultra performance liquid chromatography-quadrupole-electrostatic field orbital trap high-resolution mass spectrometry) was utilized to perform an in-depth analysis of the components in the plasma extract of BB. Leveraging network pharmacology, molecular docking analyses, and experimental validation, we initially elucidated the potential mechanisms through which BB mediates its therapeutic effects on PL-CAG at both in vivo and in vitro levels. Results: Prototype compounds of 42 blood-entering components were identified by UPLC-QE-Orbitrap-MS/MS analysis. Network pharmacology analysis and molecular docking studies indicate that the core targets are primarily enriched in the PI3K-Akt signaling pathway, and the key components, including Nepitrin, Quercetin 3-O-neohesperidoside, Rutin, and others, exhibited stable docking conformations with the first eleven pivotal targets. Both in vivo and in vitro experiments validated that BB may effectively treat PL-CAG via modulation of the PI3K-Akt signaling pathway. Conclusions: The therapeutic efficacy of BB in the management of PL-CAG may be achieved through the synergistic interaction of multiple components and targets, which may be more closely related to the inhibition of the PI3K/AKT signaling pathway. This approach will establish a solid experimental foundation and provide essential data for the clinical application of BB in treating PL-CAG, while also facilitating further research initiatives.

Sigma‐2 receptor/TMEM97 is overexpressed in many tumours, and sigma‐2 receptor ligands are under investigation for cancer therapy. We intended to evaluate the effect of PB28 on renal cancer in proliferation, migration and invasion in vitro and in vivo. Invasive renal cancer cell lines treated with PB28 (or sigma‐2 receptor antagonist 1) were subjected to cell proliferation, migration and invasion assays. The therapeutic effect of PB28 was performed on nude mice. Western blot for proteins in the PI3K‐AKT‐mTOR signalling pathway was conducted. A CCK‐8 assay was used to examine the effect of the combination of PB28 and cisplatin on renal cancer cells. Significant inhibitory effects were observed on proliferation, migration and invasion of 786‐O and ACHN cells after culturing with PB28. But, the outcomes of sigma‐2 receptor antagonist 1 presented the opposite tendency. PB28 significantly inhibited the proliferative and invasive ability of OS‐RC‐2 cells in vivo. Treatment resulted in decreased phosphorylation of constituents of the PI3K‐AKT‐mTOR pathway. The combination of PB28 and cisplatin showed enhanced efficacy in the inhibition of renal cancer cell proliferation. Taken together, PB28 inhibited the tumorigenic behaviours of renal cancer cells by regulating the PI3K‐AKT‐mTOR signalling pathway and was expected to be a sensitizer of cisplatin.

Background Mechanical inactivity rapidly induces diaphragm muscle fibres' contractile dysfunction and atrophy. Diaphragm weakness can impair respiratory function, quality of life and increase risks of morbidity and mortality. Muscle RING‐finger protein‐1 (MuRF1) expression is upregulated during denervation and muscle inactivity and is known to target key muscle proteins for degradation. We previously reported that the small‐molecule targeting MuRF1 (MyoMed‐205) protects against diaphragm contractile dysfunction and atrophy after 12 h of unilateral diaphragm denervation (UDD) in rats. In this study, we investigated the mechanisms by which MyoMed‐205 protects the diaphragm structure and function during early UDD in rats. Methods Male Wistar rats were subjected to unilateral diaphragm denervation (UDD) for 12 h. Immediately after UDD, rats received either a placebo (vehicle) or small‐molecule targeting MuRF1 (MyoMed‐205, 50 mg/kg bw), and outcomes were compared with sham‐operated controls. Diaphragm was used for histological, morphometric, transcriptomic (RNA‐seq) and protein content (Western blot) analysis. Results UDD induced diaphragm slow‐ (Type I: p = 0.03) and fast‐twitch (Type IIa: p = 0.04; Type IIb/x: p = 0.02) fibres atrophy after 12 h, which was prevented by MyoMed‐205 (p < 0.05). Mechanistically, UDD perturbed mechanisms involved with myofibre ultrastructure and contractility, mitochondrial function, proteolysis and tissue remodelling in the diaphragm. MyoMed‐205 enhanced the activation of mechanisms required for sarcomere integrity, calcium handling, antioxidant defence, chaperone‐mediated unfolded protein response and muscle growth. MyoMed‐205 also mitigated intramuscular fat deposition and pro‐fibrotic responses triggered by UDD. Conclusions Small‐molecule targeting MuRF1 (MyoMed‐205) protects against diaphragm muscle contractile dysfunction and atrophy after 12 h of UDD. Herein, we demonstrate that this protective effect involved augmented activation of signalling pathways controlling muscle structure and function, chaperone‐mediated unfolded protein and muscle growth, while mitigating intramuscular fat deposition and pro‐fibrotic responses triggered by UDD at the transcriptional and/or protein level.

QiShenYiQi pill (QSYQ), a traditional Chinese medicine, is well known for improving the myocardial remodelling, but the dose‐effect relationship of its intervention in the reparative myocardial fibrosis is still unclear. We investigated the effect of QSYQ on the reparative myocardial fibrosis in cardiac myosin‐induced rats and explored its mechanism of action by regulating autophagy. The results indicated that QSYQ increased LVEF and LVFS, and decreased the LVEDD, LVESD, HMI, LVMI, myocardial inflammation histology score, and collagen volume fraction in a dose‐dependent manner. In addition, QSYQ declined the number of autophagosomes, down‐regulated the expression of myocardial Beclin‐1 and LC3B, up‐regulated the expression of myocardial p62 and increased the ratios of myocardial p‐PI3K/PI3K, p‐Akt/Akt and p‐mTOR/mTOR. We provided evidence for that QSYQ could inhibit excessive myocardial autophagy by regulating the PI3K/Akt‐mTOR pathway and can be a potential therapeutic approach in treating the cardiovascular diseases such as myocarditis and dilated cardiomyopathy.

The study aimed to investigate the effect of α2A-adrenergic receptor (ADRA2A) on cervical cancer and the potential mechanisms of ADRA2A on phosphatidylinositol 3'-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in cervical cancer cells. In our study, ADRA2A expression was evaluated by analyzing cervical cancer RNA sequencing dataset from the GEPIA. The prognostic values of ADRA2A were evaluated by Kaplan-Meier method using the Cancer Genome Atlas (TCGA) database data. In addition, the expression of ADRA2A in cervical cancer cell lines was detected by qRT-PCR and Western blot. Subsequently, the roles of ADRA2A on cell proliferation, apoptosis, migration, invasion and senescence in HeLa and SiHa cells were evaluated. Moreover, tumorigenesis in nude mice was used to investigate the role of ADRA2A in vivo. We also detected the expression changes of key factors in PI3K/Akt/mTOR pathway after overexpression and silencing of ADRA2A in HeLa and SiHa cells. ADRA2A expression was significantly downregulated in cervical cancer tissues and cell lines. The high expression of ADRA2A was significantly associated with a better prognosis in cervical cancer patients. ADRA2A overexpression significantly suppressed cell proliferation, migration and invasion, and promoted cell senescence and apoptosis in cervical cancer cells. On the contrary, silencing ADRA2A dramatically facilitated cell proliferation, migration and invasion, and inhibited cell senescence and apoptosis in cervical cancer cells. The expressions of p-PI3K, p-AKT and p-mTOR in cervical cancer cells were notably decreased by ADRA2A overexpression and increased by silencing ADRA2A. In addition, we also confirmed that ADRA2A overexpression could suppress the xenograft tumor growth in vivo. Our study demonstrated that ADRA2A could suppress cell proliferation, migration and invasion, as well as promote cell senescence and apoptosis through inhibiting PI3K/Akt/mTOR pathway in cervical cancer.