Inhibited Tumor Cell Proliferation Research Articles

Shenqi Fuzheng injection hinders non-small cell lung cancer cell growth by regulating the Bax/Bcl-2 signaling pathway

IntroductionLung cancer (LC) is the most common solid tumor and is currently considered the primary cause of cancer-related deaths worldwide. In clinical efficacy studies, it was not difficult to find that the combination of SFI and chemotherapy could improve the general condition of patients, reduce the side effects of chemotherapy drugs, and have a cooperative antitumor effect in NSCLC patients. However, whether SFI can be used as a novel antitumor drug is still unknown.MethodsFirst, meta-analysis aimed to explore the efficacy of SFI in NSCLC patients, and SFI was identified by ultra-performance liquid chromatography‒mass spectrometry (UPLC‒MS). Cell proliferation, migration, and invasion were explored by Cell Counting Kit-8 (CCK-8), scratch healing, and Transwell assays, respectively. Cell cycle and apoptosis assays were performed by flow cytometry. Transcriptome sequencing analysis was performed in four NSCLC cell lines. Differential expression analysis was used to identify potential targets. Apoptosis-related protein levels were detected by Western blotting assays. The effects of SFI in NSCLC were further investigated by mouse xenografts.ResultsSFI could markedly improve the chemotherapy efficacy of NSCLC patients. The main active ingredients include flavonoids and terpenoids, which can effectively exert antitumor effects. SFI could not only inhibit tumor cell proliferation and cell migration/invasion but also regulate the cell cycle and promote tumor cell apoptosis. In NSCLC, SFI could enhance the transcription level of the CHOP gene, thereby upregulating the expression of the proapoptotic proteins Bax and caspase 3, and inhibiting the expression of the antiapoptotic protein Bcl-2. SFI hindered the growth of mouse NSCLC xenografts in vivo.ConclusionsSFI hindered tumor progression and might promote apoptosis by increasing the expression of Bax, caspase 3 and decreasing the level of Bcl-2 in NSCLC.

TNA-Mediated Antisense Strategy to Knockdown Akt Genes for Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) remains a significant challenge in terms of treatment, with limited efficacy of chemotherapy due to side effects and acquired drug resistance. In this study, a threose nucleic acid (TNA)-mediated antisense approach is employed to target therapeutic Akt genes for TNBC therapy. Specifically, two new TNA strands (anti-Akt2 and anti-Akt3) are designed and synthesized that specifically target Akt2 and Akt3 mRNAs. These TNAs exhibit exceptional enzymatic resistance, high specificity, enhance binding affinity with their target RNA molecules, and improve cellular uptake efficiency compared to natural nucleic acids. In both 2D and 3D TNBC cell models, the TNAs effectively inhibit the expression of their target mRNA and protein, surpassing the effects of scrambled TNAs. Moreover, when administered to TNBC-bearing animals in combination with lipid nanoparticles, the targeted anti-Akt TNAs lead to reduced tumor sizes and decreased target protein expression compared to control groups. Silencing the corresponding Akt genes also promotes apoptotic responses in TNBC and suppresses tumor cell proliferation in vivo. This study introduces a novel approach to TNBC therapy utilizing TNA polymers as antisense materials. Compared to conventional miRNA- and siRNA-based treatments, the TNA system holds promise as a cost-effective and scalable platform for TNBC treatment, owing to its remarkable enzymatic resistance, inexpensive synthetic reagents, and simple production procedures. It is anticipated that this TNA-based polymeric system, which targets anti-apoptotic proteins involved in breast tumor development and progression, can represent a significant advancement in the clinical development of effective antisense materials for TNBC, a cancer type that lacks effective targeted therapy.

Glycolytic enzyme PFKL governs lipolysis by promoting lipid droplet-mitochondria tethering to enhance β-oxidation and tumor cell proliferation.

Lipid droplet tethering with mitochondria for fatty acid oxidation is critical for tumor cells to counteract energy stress. However, the underlying mechanism remains unclear. Here, we demonstrate that glucose deprivation induces phosphorylation of the glycolytic enzyme phosphofructokinase, liver type (PFKL), reducing its activity and favoring its interaction with perilipin 2 (PLIN2). On lipid droplets, PFKL acts as a protein kinase and phosphorylates PLIN2 to promote the binding of PLIN2 to carnitine palmitoyltransferase 1A (CPT1A). This results in the tethering of lipid droplets and mitochondria and the recruitment of adipose triglyceride lipase to the lipid droplet-mitochondria tethering regions to engage lipid mobilization. Interfering with this cascade inhibits tumor cell proliferation, promotes apoptosis and blunts liver tumor growth in male mice. These results reveal that energy stress confers a moonlight function to PFKL as a protein kinase to tether lipid droplets with mitochondria and highlight the crucial role of PFKL in the integrated regulation of glycolysis, lipid metabolism and mitochondrial oxidation.

Effective glioblastoma immune sonodynamic treatment mediated by macrophage cell membrane cloaked biomimetic nanomedicines

Glioblastoma (GBM) as one of the most lethal brain tumours, remains poor therapeutic index due to its typical characters including heterogeneous, severe immune suppression as well as the existence of blood brain barrier (BBB). Immune sonodynamic (ISD) therapy combines noninvasive sonodynamic therapy with immunotherapy, which has great prospects for the combinational treatment of GBM. Herein, we develop macrophage cell membrane cloaked reactive oxygen species (ROS) responsive biomimetic nanoparticles, co-delivering of sonosensitizer Ce6 and JQ1 (a bromo-domain protein 4 (BRD4) inhibitor which can down-regulate PD-L1) and realizing potent GBM ISD therapy. The ApoE peptide decorated macrophage membrane coating endows these biomimetic nanoparticles with low immunogenicity, efficient BBB permeability, prolonged blood circulation half-live and good biocompatibility. The ROS responsive polymeric inner core could be readily degraded as triggered by excessive ROS under the ultrasound once they accumulated in tumour cells, fast release encapsulated drugs. The generation of ROS not only killed tumour cells via sonodynamic therapy, but also induced immunogenic cell death (ICD) and further activated the anti-tumour immune response. The released JQ1 inhibited tumour cell proliferation and augmented the immune activities by inhibiting the PD-L1 expression on the surface of tumour cells. The cascade sonodynamic and immune therapy resulted in significantly improved median survival time in both orthotopic GL261 and PTEN deficient immunosuppressive CT2A GBM mice models. Therefore, our developed biomimetic nanoparticle platform provides a promising combinational therapy strategy to treat immune suppressive GBM.

SLC7A11 promotes EMT and metastasis in invasive pituitary neuroendocrine tumors by activating the PI3K/AKT signaling pathway.

Invasive pituitary neuroendocrine tumors (PitNETs) are the most prevalent types of intracranial and neuroendocrine tumors. Their aggressive growth and difficulty in complete resection result in a high recurrence rate. Cystine transporter solute carrier family 7 member 11 (SLC7A11) is overexpressed in various cancers, which contributes to tumor growth, progression, and metastasis by promoting cystine uptake and glutathione biosynthesis. We identified SLC7A11 as an invasive biomarker based on three Gene Expression Omnibus cohorts. This study aimed to investigate the role of SLC7A11 in invasive PitNETs. Cell proliferation was assessed using CCK-8 and colony formation assays, while cell apoptosis was estimated with flow cytometry. Wound healing assays and transwell assays were utilized to evaluate migration and invasion ability. Our findings demonstrated that SLC7A11 was markedly upregulated in invasive PitNETs, and was associated with the invasiveness of PitNETs. Knockdown of SLC7A11 could largely suppress tumor cell proliferation, migration, and invasion, while inducing apoptosis. Furthermore, SLC7A11 depletion was implicated in regulating epithelial-mesenchymal transition and inactivating the PI3K/AKT signaling pathway. These insights suggest SLC7A11 as a potential therapeutic target for invasive PitNETs.

Traditional Chinese Medicine for Cancer Treatment.

In recent years, due to advancements in medical conditions and the development of scientific research, the fundamental research of TCM antitumor treatments has progressed from the cellular level to the molecular and genetic levels. Previous studies have demonstrated the significant role of traditional Chinese medicine (TCM) in antitumor therapy through various mechanisms and pathways. Its mechanism of action is closely associated with cancer biology across different stages. This includes inhibiting tumor cell proliferation, blocking invasion and metastasis to surrounding tissues, inducing tumor cell apoptosis, inhibiting tumor angiogenesis, regulating immune function, maintaining genome stability, preventing mutation, and regulating cell energy metabolism. The use of TCM for eliciting antitumor effects not only has a good therapeutic effect and low side effects, it also provides a solid theoretical basis for clinical treatment and medication. This paper reviews the mechanism of the antitumor effects of TCM based on tumor characteristics. Through our review, we found that TCM not only directly inhibits tumors, but also enhances the body's immunity, thereby indirectly inducing an antitumor effect. This function aligns with the TCM theory of "strengthening the body's resistance to eliminate pathogenic factors". Furthermore, TCM will play a significant role in tumor treatment in clinical settings.

Lactate dehydrogenase B as a metabolism-related marker for immunotherapy in head and neck squamous cell carcinoma

BackgroundHead and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies. Lactate dehydrogenase family genes (LDHs) play a critical role in tumor metabolism, but their functions in HNSCC have not been investigated thoroughly. Thus, we aimed to explore the value of LDHs in HNSCC. MethodsThe association between LDHs expression and mutations, methylation, copy number variations (CNVs), alternative splicing (AS) and competing endogenous RNA (ceRNA) was investigated in The Cancer Genome Atlas (TCGA). The expression level of LDHs in OSCC tissues and adjacent normal tissues was verified by qPCR. Algorithms, such as ssGSEA, ESTIMATE, xCell and TIDE were utilized to analyze the characteristics of immune infiltration. Pathway alternations were enriched by GO, GSEA and KEGG analysis. The Mantel test was employed to elucidate the correlation between metabolism and the tumor microenvironment (TME). Subsequently, MTT and colony formation assays were utilized to assess the impact of LDHB knockdown on cellular proliferation. Additionally, ATP and lactate assays were performed to examine metabolic alterations. Co-culture experiments further investigated the effect of LDHB knockdown on T cell differentiation. ResultsLDHs were completely analyzed in multiple databases, among which LDHB was differentially expressed in HNSCC and significantly associated with prognosis. Low LDHB expression had better clinicopathological characteristics. Downregulated LDHB expression was associated with enhanced immune cell infiltration and could influence tumor metabolism. Despite having worse cytotoxic T lymphocyte dysfunction, the LDHBlow group was predicted to respond more favorably to immune checkpoint inhibitors (ICIs) therapy. Moreover, the correlation between metabolism and TME was depicted. In vitro, LDHB knockdown resulted in inhibited cell proliferation, increased lactate levels and decreased ATP levels, while promoted the Th1 differentiation of T cells. ConclusionsOur study provided a comprehensive analysis of the LDHs and illustrated low LDHB expression could inhibit tumor cell proliferation and ATP production by influencing metabolism, with improved immune cell infiltration and better response to immunotherapy.

A dual gene combination therapy approach by KRAS-G12V gene editing and SLC25A22 gene silencing for KRAS-mutant colorectal cancer

KRAS gene is mutated in 40% of colorectal cancers (CRC), which induces malignant proliferation by regulating cellular nutrient metabolism and biosynthesis. It has been found that malignant proliferation of KRAS-mutant colorectal cancer relies on the upregulation of SLC25A22 protein expression, suggesting that inhibition the expression of both KRAS and SLC25A22 is a potential CRC therapeutics. Stably knocking down the oncogenic KRAS-G12V gene can achieve long-term gene therapy effects, while transient downregulation of SLC25A22, a normal functional gene most of the time, is preferred to kill tumor cells and minimize the side impact on normal cells. Here, two lipid nanoparticles (LNP) were designed to encapsulate KRAS-G12V CRISPR/Cas9 gene editing plasmids (pKRAS-LNPs) and SLC25A22 siRNA (siSLC-LNPs), respectively. Therapeutic effects of both nanoparticles alone and in combination on KRAS-G12V mutant colorectal cancer cells in vitro were first examined. The result showed that delivery of pKRAS-LNPs or siSLC-LNPs alone could effectively achieve KRAS-G12V gene editing or SLC25A22 gene silencing and inhibit tumor cell proliferation, while co-delivery of both LNPs could achieve stronger inhibition of tumor cell proliferation by inducing stronger apoptosis. Furthermore, we found that co-delivery of pKRAS-LNPs and siSLC-LNPs induced stronger apoptosis and cell proliferation inhibition compared to pKRAS&siSLC-LNPs that were constructed by pre-mixing pKRAS and siSLC and then encapsulating them. Finally, we validated that co-delivery of pKRAS-LNPs and siSLC-LNPs can achieve KRAS-G12V colorectal cancer treatment in vivo with a tumor inhibition rate of 61.15%. In summary, the delivery vectors constructed for nucleic acids targeting KRAS and SLC25A22 achieved therapeutic targeting of KRAS-G12V colorectal cancer in vitro and in vivo.

Abstract PO3-02-12: Dalpiciclib combination with letrozole as neoadjuvant therapy for HR-positive HER2-negative breast cancer: a single-arm, prospective exploratory clinical study

Abstract Background: CDK4/6 inhibitors effectively block tumor cells from progressing from the G1 phase to the S phase, thereby interrupting the cell cycle progression and inhibiting tumor cell proliferation. Dalpiciclib is a novel CDK4/6 inhibitor developed independently in China, which has been approved for use in combination with fulvestrant for the treatment of HR-positive/HER2-negative recurrent or metastatic breast cancer in patients who have experienced disease progression after prior endocrine therapy, or in combination with aromatase inhibitors as initial treatment for HR-positive/HER2-negative locally advanced or metastatic breast cancer patients. This study aims to explore the efficacy and safety of dalpiciclib in combination with letrozole as neoadjuvant therapy for HR-positive, HER2-negative breast cancer. Methods: This is a single-arm, open-label study that enrolled female breast cancer patients with early or locally advanced HR-positive, HER2-negative tumors and an ECOG performance status of 0 to 1. After enrollment, patients first received 4 cycles of dalpiciclib (150mg po qd, d1-21, q4w) in combination with letrozole as neoadjuvant therapy. Breast MRI was performed every 2 cycles, and treatment response was evaluated according to the RECIST 1.1 criteria. If patients achieved a confirmed complete response (CR) or partial response (PR) after 4 cycles, they would continue to receive an additional 4 cycles of dalpiciclib in combination with letrozole treatment. If the treatment response was stable disease (SD) or disease progression (PD), the investigator might modify other treatment regimens based on the individual circumstances of the subjects. The primary endpoint was residual cancer burden (RCB 0/I), and the secondary study endpoints were objective response rate (ORR), complete cell cycle arrest (CCCA, C1D15 Ki67≤2.7%) rate and safety. This study is registered at the Chinese Clinical Trial Registry Centre (registration No. ChiCTR2200057104). Results: From April 2022 to June 2023, a total of 38 patients were screened and enrolled in the study. All patients had ER ≥ 50%, and 84% (32/38) had Ki67 ≥ 88%. Among the 21 patients who completed the assessment after 4 cycles, the overall response rate (ORR) was 81% (17/21). Additionally, among the 22 patients who underwent C1D15 biopsy and Ki67 analysis, 55% (12/22) had C1D15 Ki67 ≤ 2.7%. After completing 8 cycles of neoadjuvant treatment with the combination of dalpiciclib and letrozole,12 patients underwent surgery. The postoperative RCB scores were as follows: 1 patient had RCB (0-I), and 11 patients had RCB (II-III). The most common adverse event was decreased neutrophil count (25/38 [66%]). Among the 38 patients, 16 (42%) experienced grade 3 or worse treatment-related adverse events. There were no occurrences of grade 4 or worse adverse events. Conclusions: The combination of dalpiciclib and letrozole has shown efficacy in downstaging and shrinking tumors in patients with early or locally advanced HR-positive/HER2-negative breast cancer. Patients who exhibit a positive response in the assessment after 4 cycles may consider it as a viable option for chemo-free neoadjuvant treatment. Citation Format: Jingruo Li, Yuanting Gu, Chuang Du, Jianhua Zhang, Yingying Zhang, Linfeng Zhang, Nan Wang, Lin Li, Fang Wang, Pengwei Lv, Hong Zong, Xinhong Pei, Bingjian Xue, Yan Wang, Dongcheng Gao. Dalpiciclib combination with letrozole as neoadjuvant therapy for HR-positive HER2-negative breast cancer: a single-arm, prospective exploratory clinical study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-02-12.

Abstract PO2-24-10: Anti-Tumorigenic Immuno-Microenvironment by AB-329, a Potent and Selective AXL inhibitor, combined with paclitaxel in Triple-Negative Breast Cancer Preclinical Model

Abstract BACKGROUND The Gas6/AXL signaling pathway plays a substantial role in cancer cell survival, proliferation, immunosuppression, and metastasis. Elevated AXL expression is associated with advanced cancer stages and decreased overall survival rates, underscoring its potential as a therapeutic target for metastatic cancers. We investigated this possibility by utilizing AB-329, a selective small molecule AXL kinase inhibitor, to treat triple-negative breast cancer (TNBC). TNBC, typified by the lack of ER, PR, and HER2 expression, frequently displays mesenchymal characteristics and carries a significant risk of metastasis and an immunosuppressive tumor microenvironment. METHODS We assessed AXL protein expression in 28 human and 11 mouse breast cancer cell lines using Western blotting. The Microarray database was utilized to examine AXL gene expression in 40 human breast cancer cells. The Sulforhodamine B proliferation and soft agar assays measured the antiproliferative effect of AB-329 in TNBC cell lines. The in vitro anti-metastatic impact of AB-329 was evaluated through migration and invasion assays. We appraised the anti-tumor effects of AB-329 in combination with paclitaxel using 4T1 and E0771-LMB mouse TNBC xenograft models. We used FACS and CIBERSORTx to perform immune cell type profiling in E0771-LMB xenograft tumor tissues. To understand AB-329’s immunomodulatory effects in tumors, single-cell RNA sequencing was conducted in a humanized mouse model with SUM149 human TNBC xenografts. RESULTS Microarray data revealed higher AXL expression in TNBC cells compared to non-TNBC cells. Western blotting supported this, showing higher AXL protein expression, particularly in basal and mesenchymal subtypes of TNBC cells, compared to luminal breast cancer cells. AB-329 presented moderate antiproliferative effects as a monotherapy in the TNBC cell lines tested, with half-maximal inhibitory concentrations exceeding 5 µM. Nevertheless, combining AB-329 with paclitaxel resulted in significant growth inhibition in all tested TNBC cell lines (p < 0.05). Importantly, AB-329 alone could inhibit TNBC migration and invasion at a concentration of 1 µM (p < 0.01) and showed enhanced inhibition rates when paired with paclitaxel (p < 0.05). The combination of AB-329 and paclitaxel considerably reduced tumor growth in the 4T1 and E0771-LMB xenograft models compared to paclitaxel or AB-329. Total RNA sequencing and CIBERSORTx analysis indicated that the AB-329 and paclitaxel combination increased Natural Killer (NK) cells’ infiltration into E0771-LMB mouse TNBC xenograft tumors compared to single agent-treated tumors. A nearly 2.5-fold increase in NKT cell infiltration was also detected with AB-329 treatment compared to Control in SUM149 human TNBC xenografts. CONCLUSIONS Our preclinical data suggest that AB-329, an AXL inhibitor, could synergize effectively with paclitaxel in TNBC treatment, notably inhibiting tumor cell proliferation and migration while enhancing NK cell infiltration. Intriguingly, we observed an increased infiltration of NKT cells into tumors following AB-329 treatment, which may promote an anti-tumorigenic immuno-microenvironment. These results underscore the necessity for further investigation into the role of AB-329 in modulating the tumor immuno-microenvironment through AXL pathway inhibition and accentuate the potential for combining AB-329 with immunotherapy. Citation Format: Dileep Reddy Rampa, Jon Fuson, Huey Liu, Max Pan, Naoto Ueno, Jangsoon Lee. Anti-Tumorigenic Immuno-Microenvironment by AB-329, a Potent and Selective AXL inhibitor, combined with paclitaxel in Triple-Negative Breast Cancer Preclinical Model [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-24-10.

A potassium-chloride co-transporter with altered genome architecture functions as a suppressor in glioma.

Gliomas, the most lethal tumours in brain, have a poor prognosis despite accepting standard treatment. Limited benefits from current therapies can be attributed to genetic, epigenetic and microenvironmental cues that affect cell programming and drive tumour heterogeneity. Through the analysis of Hi-C data, we identified a potassium-chloride co-transporter SLC12A5 associated with disrupted topologically associating domain which was downregulated in tumour tissues. Multiple independent glioma cohorts were included to analyse the characterization of SLC12A5 and found it was significantly associated with pathological features, prognostic value, genomic alterations, transcriptional landscape and drug response. We constructed two SLC12A5 overexpression cell lines to verify the function of SLC12A5 that suppressed tumour cell proliferation and migration invitro. In addition, SLC12A5 was also positively associated with GABAA receptor activity and negatively associated with pro-tumour immune signatures and immunotherapy response. Collectively, our study provides a comprehensive characterization of SLC12A5 in glioma and supports SLC12A5 as a potential suppressor of disease progression.

Correlation of NAT10 expression with clinical data and survival profiles in esophageal squamous cell carcinoma patients, and its impact on cell proliferation and apoptosis.

This study investigates the association between NAT10 expression and clinical parameters while assessing prognostic outcomes in esophageal squamous cell carcinoma (ESCC) patients. Furthermore, the study seeks to elucidate the functional role of NAT10 in neoplastic cell proliferation and apoptosis. NAT10 expression was assessed in ESCC tissue microarrays through immunohistochemistry (IHC) tests. We employed SPSS software to analyze the correlation between NAT10 staining data, clinical indicators, and their implications for patient prognosis. Small interference RNA (siRNA) was utilized to inhibit NAT10 expression in two esophageal cancer cell lines, TE-1 and KYSE150. Subsequently, we meticulously quantified and compared cellular proliferation and apoptotic ratios among experimental groups. NAT10, Ki67, and Caspase3 expression levels in different groups were evaluated using quantitative polymerase chain reaction (qPCR) and Western blot (WB) assays. Statistical analyses were conducted using GraphPad Prism software, with significance at p<0.05. Our findings indicate that NAT10 is overexpressed in ESCC tissues and exhibits a significant correlation with tumor diameter and overall patient survival. Decreasing NAT10 expression led to the inhibition of tumor cell proliferation and the promotion of apoptosis. Furthermore, siRNA-mediated NAT10 inhibition resulted in the downregulation of Ki67 expression and the concomitant upregulation of Caspase3. The observed overexpression of NAT10 in ESCC tissues is associated with larger tumor diameters and reduced patient survival. NAT10 appears to play a pivotal role in the progression of esophageal cancer by influencing cell proliferation and apoptosis. These findings suggest potential clinical implications, with Ki67 and Caspase3 potentially participating in this intricate molecular biological process.

Novel combinatorial autophagy inhibition therapy for triple negative breast cancers

BackgroundTriple negative breast cancer (TNBC) has the worst prognosis among breast cancer subtypes. It is characterized by lack of estrogen, progesterone and human epidermal growth factor 2 receptors, and thus, have limited therapeutic options. Autophagy has been found to be correlated with poor prognosis and aggressive behaviour in TNBC. This study aimed to target autophagy in TNBC via a novel approach to inhibit TNBC progression. MethodsImmunoblotting and confocal microscopy were carried out to examine the effect of tumor microenvironmental stressors on autophagy. Cellular proliferation and migration assays were used to test the effect of different autophagy inhibitors and standard chemotherapy alone or in combination. In vivo xenograft mouse model was utilized to assess the effect of autophagy inhibitors alone or in combination with Paclitaxel. High resolution mass spectrometry based proteomic analysis was performed to explore the mechanisms behind chemoresistance in TNBC. Lastly, immunohistochemistry was done to assess the correlation between autophagy related proteins and clinical characteristics in TNBC tissue specimens. ResultsMetabolic stressors were found to induce autophagy in TNBC cell lines. Autophagy initiation inhibitors, SAR405 and MRT68921, showed marked synergy in their anti-proliferative activity in both chemosensitive and chemoresistant TNBC cell models. Paradoxically, positive expression of autophagosome marker LC3 was shown to be associated with better overall survival of TNBC patients. ConclusionIn this study, a novel combination between different autophagy inhibitors was identified which inhibited tumor cell proliferation in both chemosensitive and chemoresistant TNBC cells and could result in development of a novel treatment modality against TNBC.

ACP-DRL: an anticancer peptides recognition method based on deep representation learning.

Cancer, a significant global public health issue, resulted in about 10 million deaths in 2022. Anticancer peptides (ACPs), as a category of bioactive peptides, have emerged as a focal point in clinical cancer research due to their potential to inhibit tumor cell proliferation with minimal side effects. However, the recognition of ACPs through wet-lab experiments still faces challenges of low efficiency and high cost. Our work proposes a recognition method for ACPs named ACP-DRL based on deep representation learning, to address the challenges associated with the recognition of ACPs in wet-lab experiments. ACP-DRL marks initial exploration of integrating protein language models into ACPs recognition, employing in-domain further pre-training to enhance the development of deep representation learning. Simultaneously, it employs bidirectional long short-term memory networks to extract amino acid features from sequences. Consequently, ACP-DRL eliminates constraints on sequence length and the dependence on manual features, showcasing remarkable competitiveness in comparison with existing methods.

GSH-responsive degradable nanodrug for glucose metabolism intervention and induction of ferroptosis to enhance magnetothermal anti-tumor therapy

The challenges associated with activating ferroptosis for cancer therapy primarily arise from obstacles related to redox and iron homeostasis, which hinder the susceptibility of tumor cells to ferroptosis. However, the specific mechanisms of ferroptosis resistance, especially those intertwined with abnormal metabolic processes within tumor cells, have been consistently underestimated. In response, we present an innovative glutathione-responsive magnetocaloric therapy nanodrug termed LFMP. LFMP consists of lonidamine (LND) loaded into PEG-modified magnetic nanoparticles with a Fe3O4 core and coated with disulfide bonds-bridged mesoporous silica shells. This nanodrug is designed to induce an accelerated ferroptosis-activating state in tumor cells by disrupting homeostasis. Under the dual effects of alternating magnetic fields and high concentrations of glutathione in the tumor microenvironment, LFMP undergoes disintegration, releasing drugs. LND intervenes in cell metabolism by inhibiting glycolysis, ultimately enhancing iron death and leading to synthetic glutathione consumption. The disulfide bonds play a pivotal role in disrupting intracellular redox homeostasis by depleting glutathione and inactivating glutathione peroxidase 4 (GPX4), synergizing with LND to enhance the sensitivity of tumor cells to ferroptosis. This process intensifies oxidative stress, further impairing redox homeostasis. Furthermore, LFMP exacerbates mitochondrial dysfunction, triggering ROS formation and lactate buildup in cancer cells, resulting in increased acidity and subsequent tumor cell death. Importantly, LFMP significantly suppresses tumor cell proliferation with minimal side effects both in vitro and in vivo, exhibiting satisfactory T2-weighted MR imaging properties. In conclusion, this magnetic hyperthermia-based nanomedicine strategy presents a promising and innovative approach for antitumor therapy.Graphical

Discovery of a novel small-molecule activator of SIRT3 that inhibits cell proliferation and migration by apoptosis and autophagy-dependent cell death pathways in colorectal cancer

Colorectal cancer (CRC) is well known as a prevalent malignancy affecting the digestive tract, yet its precise etiological determinants remain to be elusive. Accordingly, identifying specific molecular targets for colorectal cancer and predicting potential malignant tumor behavior are potential strategies for therapeutic interventions. Of note, apoptosis (type I programmed cell death) has been widely reported to play a pivotal role in tumorigenesis by exerting a suppressive effect on cancer development. Moreover, autophagy-dependent cell death (type II programmed cell death) has been implicated in different types of human cancers. Thus, investigating the molecular mechanisms underlying apoptosis and autophagy-dependent cell death is paramount in treatment modalities of colorectal cancer. In this study, we uncovered that a new small-molecule activator of SIRT3, named MY-13, triggered both autophagy-dependent cell death and apoptosis by modulating the SIRT3/Hsp90/AKT signaling pathway. Consequently, this compound inhibited tumor cell proliferation and migration in RKO and HCT-116 cell lines. Moreover, we further demonstrated that the small-molecule activator significantly suppressed tumor growth in vivo. In conclusion, these findings demonstrate that the novel small-molecule activator of SIRT3 may hold a therapeutic potential as a drug candidate in colorectal cancer.

Fructose-1,6-bisphosphatase 1 dephosphorylates and inhibits TERT for tumor suppression.

Telomere dysfunction is intricately linked to the aging process and stands out as a prominent cancer hallmark. Here we demonstrate that telomerase activity is differentially regulated in cancer and normal cells depending on the expression status of fructose-1,6-bisphosphatase 1 (FBP1). In FBP1-expressing cells, FBP1 directly interacts with and dephosphorylates telomerase reverse transcriptase (TERT) at Ser227. Dephosphorylated TERT fails to translocate into the nucleus, leading to the inhibition of telomerase activity, reduction in telomere lengths, enhanced senescence and suppressed tumor cell proliferation and growth in mice. Lipid nanoparticle-mediated delivery of FBP1 mRNA inhibits liver tumor growth. Additionally, FBP1 expression levels inversely correlate with TERT pSer227 levels in renal and hepatocellular carcinoma specimens and with poor prognosis of the patients. These findings demonstrate that FBP1 governs cell immortality through its protein phosphatase activity and uncover a unique telomerase regulation in tumor cells attributed to the downregulation or deficiency of FBP1 expression.

Research Progress on Anti-tumor Mechanism of Artesunate Combined Drugs

Artesunate (ART) is a semi-synthetic artemisinin derivative of hemiterpene lactones, which is widely used in clinical antimalarial therapy. In recent years, studies have shown that artesunate also has anti-inflammatory, anti-tumor, anti-fibrosis, antiviral, antibacterial, immunomodulatory and other pharmacological activities. Artesunate can play an anti-tumor role by inhibiting tumor cell proliferation, invasion and migration, promoting tumor cell apoptosis and blocking cell cycle. At the same time, when combined with other anti-tumor drugs, it can enhance the anti-tumor efficacy, shorten the duration of administration, reduce the dose and adverse reactions. In this paper, the main keywords of "artesunate", "pharmacology", "anti-tumor" and "combined drug" were searched and integrated in Pubmed, Web of Science and CNKI electronic databases to review the anti-tumor mechanism of artesunate combined with other drugs in recent 5 years. The prospect of clinical application of artesunate as an antitumor drug was prospected to provide some theoretical basis for further rational development and utilization of artesunate and new drug research and development.

Computational identification and experimental verification of a novel signature based on SARS-CoV-2-related genes for predicting prognosis, immune microenvironment and therapeutic strategies in lung adenocarcinoma patients.

Early research indicates that cancer patients are more vulnerable to adverse outcomes and mortality when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nonetheless, the specific attributes of SARS-CoV-2 in lung Adenocarcinoma (LUAD) have not been extensively and methodically examined. We acquired 322 SARS-CoV-2 infection-related genes (CRGs) from the Human Protein Atlas database. Using an integrative machine learning approach with 10 algorithms, we developed a SARS-CoV-2 score (Cov-2S) signature across The Cancer Genome Atlas and datasets GSE72094, GSE68465, and GSE31210. Comprehensive multi-omics analysis, including assessments of genetic mutations and copy number variations, was conducted to deepen our understanding of the prognosis signature. We also analyzed the response of different Cov-2S subgroups to immunotherapy and identified targeted drugs for these subgroups, advancing personalized medicine strategies. The expression of Cov-2S genes was confirmed through qRT-PCR, with GGH emerging as a critical gene for further functional studies to elucidate its role in LUAD. Out of 34 differentially expressed CRGs identified, 16 correlated with overall survival. We utilized 10 machine learning algorithms, creating 101 combinations, and selected the RFS as the optimal algorithm for constructing a Cov-2S based on the average C-index across four cohorts. This was achieved after integrating several essential clinicopathological features and 58 established signatures. We observed significant differences in biological functions and immune cell statuses within the tumor microenvironments of high and low Cov-2S groups. Notably, patients with a lower Cov-2S showed enhanced sensitivity to immunotherapy. We also identified five potential drugs targeting Cov-2S. In vitro experiments revealed a significant upregulation of GGH in LUAD, and its knockdown markedly inhibited tumor cell proliferation, migration, and invasion. Our research has pioneered the development of a consensus Cov-2S signature by employing an innovative approach with 10 machine learning algorithms for LUAD. Cov-2S reliably forecasts the prognosis, mirrors the tumor's local immune condition, and supports clinical decision-making in tumor therapies.

Cordyceps sinensis relieves non-small cell lung cancer by inhibiting the MAPK pathway

ObjectiveTo determine the pharmacodynamic mechanism underlying Cordyceps sinensis relief in a murine model of non-small cell lung cancer (NSCLC).MethodsWe created a murine model of NSCLC and studied the potential molecular mechanism by which C. sinensis relieved NSCLC using a combination of transcriptomics, proteomics, and experimental validation.ResultsC. sinensis markedly suppressed the fluorescence values in mice with NSCLC, improved the pathologic morphology of lung tissue, ameliorated inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-10, and the oxidative stress indicators superoxide dismutase, malondialdehyde, and glutathione peroxidase). Transcriptomics results showed that the therapeutic effect of C. sinensis was primarily involved in the differentiation and activation of T cells. Based on the proteomic results, C. sinensis likely exerted a protective effect by recruiting immune cells and suppressing tumor cell proliferation via the MAPK pathway. Finally, the experimental validation results indicated that C. sinensis significantly decreased the VEGF and Ki67 expression, downregulated RhoA, Raf-1, and c-fos expression, which are related to cell migration and invasion, increased the serum concentration of hematopoietic factors (EPO and GM-CSF), and improved the percentage of immune cells (natural killer cells, dendritic cells, and CD4+ and CD8+ lymphocytes), which enhanced immune function.ConclusionsBased on our preclinical study, C. sinensis was shown to exert a protective effect on NSCLC, primarily by inhibiting the MAPK pathway.