Anti-Cancer Drugs最新文献

{"title":"Activation of the caspase-1/gasdermin D pathway via α-linolenic acid-mediated GPR120 signaling induces pyroptosis and suppresses ovarian cancer tumor growth.","authors":"Shijie Sun, Li Qian","doi":"10.1097/CAD.0000000000001789","DOIUrl":"10.1097/CAD.0000000000001789","url":null,"abstract":"<p><p>To investigate the role and underlying mechanism of α-linolenic acid (ALA) in ovarian cancer (OC), particularly its relationship with pyroptosis and the GPR120/caspase-1/Gasdermin D (GSDMD) pathway. Human OC cell lines (SKOV3, A2780), THP-1 monocytes, and SKOV3 subcutaneous xenograft models in nude mice were employed. Key assays included cell counting kit-8 (CCK-8) for cell viability, lactate dehydrogenase release for membrane damage detection, ELISA for Interleukin-1β (IL-1β) and IL-18 measurement, Western blot and quantitative polymerase chain reaction (qPCR) for analyzing pyroptosis-related molecules, molecular docking for ALA-GPR120 binding, and flow cytometry. Mice were administered ALA at a dose of 50 mg/kg by intraperitoneal injection, twice weekly for 4 weeks, or saline. ALA induced pyroptosis in OC cells both in vitro and in vivo, accompanied by increased membrane damage, elevated levels of IL-1β and IL-18, and activation of pyroptosis-related molecules. It targeted and inhibited GPR120 to activate the caspase-1/GSDMD pathway, with GSDMD identified as a critical effector. ALA also promoted M1 macrophage polarization and inhibited OC cell activity. In vivo, ALA reduced tumor size, upregulated pyroptosis markers, downregulated GPR120, and caused no significant toxicity. ALA induces OC cell pyroptosis and modulates the tumor microenvironment via the GPR120/caspase-1/GSDMD pathway, safely inhibiting OC growth. This reveals a novel mechanism, supporting ALA as a potential therapeutic candidate for OC, though further research into downstream regulation is required.</p>","PeriodicalId":7969,"journal":{"name":"Anti-Cancer Drugs","volume":" ","pages":"190-203"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12851550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apatinib triggers ferroptosis in gastric cancer via HDAC1/HIF1α/CA9 signaling axis.","authors":"Lijuan Meng, Lei Cao, Yueyao Lu, Lixin Yang, Weiyou Zhu","doi":"10.1097/CAD.0000000000001776","DOIUrl":"10.1097/CAD.0000000000001776","url":null,"abstract":"<p><p>Gastric cancer (GC) poses significant therapeutic challenges due to frequent late-stage diagnosis and limited treatment efficacy. Although Apatinib demonstrates clinical benefits in GC, acquired resistance remains problematic. Ferroptosis induction represents a promising strategy to overcome such resistance. Integrated computational target prediction (SwissTargetPrediction) and ferroptosis suppressor gene screening (FerrDb) identified carbonic anhydrase IX (CA9) as Apatinib's putative target. Functional validation employed EdU, Transwell, sphere-formation, and flow cytometry assays. Ferroptosis markers [Fe²⁺, reactive oxygen species (ROS), ACSL4, and GPX4] were quantified via specific kits and western blotting. Histone deacetylase 1 (HDAC1)/hypoxia inducible factor 1α (HIF1α)/CA9 axis regulation was assessed through overexpression, siRNA knockdown, and immunoprecipitation. Apatinib significantly suppressed GC cell proliferation, migration, and stemness while promoting apoptosis. It induced ferroptosis via Fe²⁺/ROS accumulation and abnormal ACSL4/GPX4 expression. Mechanistically, Apatinib downregulated HDAC1, triggering HIF1α ubiquitination and subsequent CA9 suppression. HDAC1 overexpression reversed Apatinib-induced ferroptosis and antitumor effects, whereas HIF1α knockdown abrogated this rescue. This study elucidates a novel HDAC1/HIF1α/CA9 axis through which Apatinib induces ferroptosis. Targeting this pathway offers translational potential for overcoming Apatinib resistance in GC therapy.</p>","PeriodicalId":7969,"journal":{"name":"Anti-Cancer Drugs","volume":" ","pages":"169-180"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical importance of the interactions between the TGF-β1/SMAD and NF-κB pathways in colorectal cancer and the study of the synergistic regulatory mechanism of the STAT3-mediated pathway.","authors":"Huang Chao, Haosheng Liu, Weizeng Shen","doi":"10.1097/CAD.0000000000001802","DOIUrl":"10.1097/CAD.0000000000001802","url":null,"abstract":"<p><p>This study aimed to explore the clinical significance and potential mechanisms of the transforming growth factor- β1 (TGF-β1)/small mother against decapentaplegic (SMAD) and nuclear factor kappa B (NF-κB) pathways in colorectal cancer (CRC). Transcriptomic and clinical data of CRC patients were retrieved from TCGA and GEO databases, analyzed via TCGAbiolinks, GEPIA 2, KEGG, and GO. A total of 275 colon cancer and 92 rectal cancer samples were included. Results showed TβR2 and SMAD2 expression was significantly associated with CRC pathological stage ( P  < 0.05), while low TGF-β1, TβR1, and TβR2 expression correlated with longer disease-free survival (DFS, P  < 0.05). Pathway component correlations differed between normal and cancerous tissues; high co-expression of NF-κB1 and SMAD2 linked to longer DFS in rectal cancer ( P  < 0.05). Signal transducer and activator of transcription 3 (STAT3) strongly correlated with NF-κB1, SMAD2/4 (R = 0.7, 0.63, 0.65; P  < 0.001), and combinations of NF-κB1 with SMAD2/SMAD4 showed strong correlations with STAT3 (R = 0.73; P  < 0.001). NF-κB1 combined with SMAD2 has prognostic value for rectal cancer, and STAT3 may be a common upstream transcription factor regulating both pathways.</p>","PeriodicalId":7969,"journal":{"name":"Anti-Cancer Drugs","volume":" ","pages":"204-216"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145817483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The evolving landscape of KRAS-targeted therapy: mechanisms of resistance and emerging strategies.","authors":"Daniel F Pilco-Janeta, Myriam De la Cruz-Puebla","doi":"10.1097/CAD.0000000000001801","DOIUrl":"10.1097/CAD.0000000000001801","url":null,"abstract":"<p><p>Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are among the most common oncogenic drivers in human cancer and are associated with poor prognosis, limited therapeutic options, and frequent resistance to standard treatments. The approval of the first direct KRAS G12C inhibitors demonstrated that mutant KRAS can be targeted clinically, but their efficacy is restricted to a narrow allelic subset and is limited by adaptive resistance. This review summarizes recent advances in KRAS-targeted drug development beyond G12C and outlines emerging strategies designed to improve therapeutic outcomes. A comprehensive literature review was conducted using preclinical and clinical data from studies investigating KRAS inhibitors, rat sarcoma (RAS) pathway modulators, and rational drug combinations. Particular attention was given to allele-specific agents, pan-RAS inhibitors, feedback signaling mechanisms, and resistance biology. Next-generation KRAS inhibitors targeting non-G12C alleles, including KRAS G12D selective agents, have demonstrated potent preclinical activity but remain susceptible to feedback mitogen-activated protein kinase (MAPK) reactivation. Pan-RAS inhibitors that bind the active RAS-GTP state show activity across multiple alleles and tumor types, although toxicity and therapeutic window remain key concerns. Indirect strategies targeting SHP2, SOS1, and downstream MAPK components enhance pathway suppression and delay resistance, especially in combination with direct KRAS inhibitors. Resistance mechanisms encompass secondary KRAS mutations, bypass signaling through alternative RAS isoforms, and activation of parallel pathways. Comutations such as STK11 or KEAP1 further influence therapeutic response and immune contexture. KRAS-directed therapy is rapidly expanding beyond G12C, with allele-specific inhibitors, pan-RAS approaches, and rational combinations offering new opportunities for broader clinical benefit. Ongoing challenges include toxicity management, resistance evolution, and the development of predictive biomarkers to guide therapy selection.</p>","PeriodicalId":7969,"journal":{"name":"Anti-Cancer Drugs","volume":" ","pages":"238-244"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145817433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distribution of side effects of anti-EGFR treatments in patients with metastatic colorectal cancer and evaluation of their relationship with survival.","authors":"Mert Erciyestepe, Okan Aydin, Sermin Dinc Sonusen, Ahmet Emin Ozturk, Emir Celik, Muhammed Mustafa Atci, Kayhan Erturk","doi":"10.1097/CAD.0000000000001755","DOIUrl":"10.1097/CAD.0000000000001755","url":null,"abstract":"<p><p>Many previous studies have investigated cetuximab and panitumumab's efficacy, safety, and side effects. Only a few studies have evaluated the relationship between toxicity and survival. Therefore, we conducted this study to examine the relationship between the side effects of anti-EGFR agents and survival in metastatic colorectal cancer patients. Our study is a single-center retrospective analysis of the medical records of 100 metastatic colorectal cancer patients between September 2014 and September 2023. Overall survival (OS) was found to be statistically significantly longer in patients who developed skin toxicity during anti-EGFR treatment (26.0 vs. 70.0 months) ( P  < 0.001). Similarly, OS was significantly better in patients with hypomagnesemia ( P  < 0.001) and constipation ( P  < 0.001) side effects. In contrast, OS was significantly worse in patients with lung toxicity ( P  = 0.016). Ocular side effects during anti-EGFR treatment did not affect OS statistically significantly ( P  = 0.268). The median PFS of patients with skin toxicity with anti-EGFR agents and hypomagnesemia in first-line treatment was 22.0 months (19.4-24.5) and 21.0 months (18.2-23.8), respectively ( P  = 0.002, P  = 0.022). In the second line, the median PFS of patients with skin toxicity and patients with hypomagnesemia who received anti-EGFR therapy was 19.0 months (6.2-31.8) and 17.0 months (8.4-25.6), respectively ( P  = 0.013, P  = 0.037). In our study, it was found that skin toxicity and hypomagnesemia positively affected both OS and PFS. OS was longer in patients with constipation, and OS was shorter in patients with lung toxicity. We suggest that survival might be predicted by monitoring side effects of these therapeutics; therefore, studies with larger cohorts are required.</p>","PeriodicalId":7969,"journal":{"name":"Anti-Cancer Drugs","volume":" ","pages":"93-101"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum heat shock protein family A member 9 protein as a biomarker for bortezomib resistance and poor prognosis in patients with multiple myeloma.","authors":"Lin Chen, Shuang Gao, Li Lin, Su Liu, Jing Ma, Zhiying Zhang, Qian Li","doi":"10.1097/CAD.0000000000001764","DOIUrl":"10.1097/CAD.0000000000001764","url":null,"abstract":"<p><p>Bortezomib resistance in multiple myeloma (MM) is a significant clinical challenge that limits the long-term effectiveness. Currently, there is a lack of reliable biomarkers to predict bortezomib resistance. Previous studies reported that several proteins regulate bortezomib resistance through targeting ubiquitin-proteasome pathways, including heat shock protein family A member 9 (HSPA9), dickkopf Wnt signaling pathway inhibitor 1 (DKK1), proteasome 26S subunit non-ATPase 14 (PSMD14), and tripartite motif containing 21 (TRIM21). In our study, we aimed to analyze the expression of these proteins in MM patients and evaluate their potential as biomarkers for bortezomib resistance. Our study enrolled 46 newly diagnosed MM patients (38 bortezomib-sensitive and eight bortezomib-resistant patients) and 52 healthy controls, and serum samples were collected from the patients before initial treatments. The levels of HSPA9, DKK1, PSMD14, and TRIM21 proteins in serum samples were measured using ELISA. The diagnostic power of HSPA9 protein for bortezomib resistance was evaluated through receiver operating characteristic curves combined with the area under curve (AUC). The correlation between HSPA9 protein and clinicopathological features was examined using the chi-square test, and Kaplan-Meier method and Cox regression analysis were applied to assess prognostic value. Compared with healthy controls, increased HSPA9 and DKK1, but decreased TRIM21 protein expression, were observed in serum samples from MM patients. There was no statistical difference in PSMD14 protein expression between the two groups. Notably, compared with bortezomib-sensitive patients, only HSPA9 protein was found to be upregulated in bortezomib-resistant patients, whereas no differences were found in the other proteins. Furthermore, the AUC of serum HSPA9 for differentiating MM patients from healthy controls was 0.906 [95% confidence interval (CI): 0.843-0.968]. And serum HSPA9 expression could effectively differentiate bortezomib-resistant MM patients from bortezomib-sensitive MM patients, with an AUC of 0.845 (95% CI: 0.734-0.957). In addition, elevated serum HSPA9 expression positively correlated with advanced International Staging System stage, increased β2-MG, abnormal immunoglobulin, and bortezomib resistance. Higher serum HSPA9 was linked to shorter overall survival rate and independently predicted poor prognosis. Our study demonstrated that elevated serum HSPA9 protein serves as a potential biomarker for bortezomib resistance and poor prognosis in MM patients.</p>","PeriodicalId":7969,"journal":{"name":"Anti-Cancer Drugs","volume":" ","pages":"102-109"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12736419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145013651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adiponectin Receptor 1-vascular endothelial growth factor axis mediates resistance to epidermal growth factor receptor-targeted therapy in nasopharyngeal carcinoma.","authors":"Zilu Cheng, Xiaohong Peng, Shuting Wu, Wanxia Li, Xiong Liu, Guohua Zhang","doi":"10.1097/CAD.0000000000001766","DOIUrl":"10.1097/CAD.0000000000001766","url":null,"abstract":"<p><p>Nasopharyngeal carcinoma (NPC) is highly prevalent in Southeast Asia and southern China, with most patients diagnosed at advanced stages. Although epidermal growth factor receptor (EGFR)-targeted therapies have shown clinical promise, their long-term efficacy is limited. This study explores the regulatory role of AdipoR1 in EGFR-targeted therapy response and evaluates adiponectin as a potential strategy to overcome treatment resistance. NPC cell lines (5-8F and CNE1) were treated with nimotuzumab for short (24 h) and long (72 h) durations. mRNA and protein expression of vascular endothelial growth factor (VEGF), AdipoR1/R2, and other pathway components were assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. Adiponectin was applied to explore its regulatory role in VEGF expression and EGFR signaling. Prolonged treatment of NPC cells with nimotuzumab inhibited EGFR downstream signaling [protein kinase B, mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase], reduced cell invasion and migration initially, but invasive capacity gradually recovered over time. VEGF expression remained unchanged at 24 h but significantly increased after 72 h, promoting angiogenesis in cocultured HUVECs. Long-term nimotuzumab exposure downregulated AdipoR1 expression, while adiponectin restored AdipoR1 and VEGF levels with decreased mTOR expression, not EGFR, indicating that the mTOR pathway may mediate this regulation. In addition, nimotuzumab elevated the expression of lipid metabolism-related genes, FABP4 and CD36, which was mitigated by A-PN cotreatment. Prolonged EGFR-targeted therapy in NPC upregulates VEGF via AdipoR1 downregulation, reducing treatment efficacy. Adiponectin restores AdipoR1, suppresses VEGF, and reverses this effect, possibly through mTOR inhibition, suggesting a potential strategy to improve long-term therapeutic outcomes.</p>","PeriodicalId":7969,"journal":{"name":"Anti-Cancer Drugs","volume":" ","pages":"146-156"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145426567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"9-Methoxycamptothecin induces proliferating cell nuclear antigen associated factor 15 mediated proliferation inhibition, DNA damage, and apoptosis in melanoma cells.","authors":"Yacong Ji, Chongyang Li, Han Hao, Yang Liu, Yan Mao, Yanli Zhang, Leiyang Guo, Shaomin Shi","doi":"10.1097/CAD.0000000000001788","DOIUrl":"10.1097/CAD.0000000000001788","url":null,"abstract":"<p><p>Melanoma is one of the most lethal forms of skin cancer, driving continuous research efforts to discover effective therapeutic strategies. Phytochemicals are promising for antimelanoma drug development because of their multitarget bioactivities. 9-Methoxycamptothecin (MCPT), a plant-origin compound, has demonstrated potent anticancer activity against various human cancers; however, its inhibitory effects on melanoma and the underlying molecular mechanisms remain incompletely understood. In this research, human melanoma cell lines (A375, SKMEL28) were treated with MCPT. Cell proliferation was evaluated using MTT and clonogenic assays. Cell cycle and apoptosis were assessed by flow cytometry. The MCPT-induced DNA damage in melanoma cells was observed via immunofluorescence staining of γ-H2AX. Protein expression was analyzed by western blotting. Proliferating cell nuclear antigen associated factor 15 (PAF15) was overexpressed via lentiviral transduction to evaluate its functional role in MCPT response. The antimelanoma effect of MCPT in vitro was studied in BALB/c nude mice bearing subcutaneous tumors from A375 cells. The results showed that MCPT suppressed melanoma cell proliferation via inducing the G2/M phase cell cycle arrest. Meanwhile, MCPT induces caspase-dependent apoptosis and DNA damage in melanoma cells. In vivo , MCPT effectively inhibited the growth of melanoma xenografts. Crucially, these MCPT-mediated effects were partly rescued by exogenous PAF15 overexpression. In conclusion, MCPT exerts antimelanoma effects by inhibiting proliferation, inducing cell cycle arrest, DNA damage, and apoptosis. Importantly, these effects are critically mediated through the downregulation of PAF15.</p>","PeriodicalId":7969,"journal":{"name":"Anti-Cancer Drugs","volume":" ","pages":"157-168"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145429986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A genome-wide screen identified ARHGAP35 as a regulator of regorafenib resistance in liver cancer.","authors":"Kun Chen, Miaomiao Zhang, Yuexin Liu, Zhengnan Dong, Yaoji Liang, Jinzhang Zeng, Jie Liu","doi":"10.1097/CAD.0000000000001775","DOIUrl":"10.1097/CAD.0000000000001775","url":null,"abstract":"<p><p>Regorafenib, a multikinase inhibitor, is widely used to treat hepatocellular carcinoma. However, chemoresistance poses a significant challenge to its long-term efficacy. This study conducted a genome-wide CRISPR/Cas9 knockout screen in liver cancer cell lines to identify key regulators of regorafenib resistance and elucidate the underlying molecular mechanisms. The screen identified ARHGAP35 as a critical negative regulator of regorafenib resistance. ARHGAP35 depletion conferred resistance in HepG2 and Huh7 cells, while regorafenib-resistant variants (HepG2-R and Huh7-R) exhibited decreased ARHGAP35 expression. Reintroducing ARHGAP35 restored drug sensitivity. Further analysis revealed that reduced ARHGAP35 expression facilitated epithelial-mesenchymal transition (EMT) by activating the RhoA signaling pathway. Notably, RhoA inhibition reversed EMT and restored regorafenib sensitivity. These findings highlight ARHGAP35 as a key modulator of regorafenib resistance through RhoA suppression, offering potential therapeutic targets to combat chemoresistance in liver cancer.</p>","PeriodicalId":7969,"journal":{"name":"Anti-Cancer Drugs","volume":" ","pages":"110-119"},"PeriodicalIF":2.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145426539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel anticancer natural product SP09 selectively targets KRAS-mutant NSCLC through LKB1/AMPK/mTOR modulation: implications for novel therapeutic development.","authors":"Peng Yue, Chitin Hon, Xiaoping Zhao, Fayaz Ali, Jiayi Sun, Jiyou Kou","doi":"10.1097/CAD.0000000000001773","DOIUrl":"10.1097/CAD.0000000000001773","url":null,"abstract":"<p><p>KRAS -mutant non-small cell lung cancer (NSCLC) remains a major therapeutic challenge due to the paucity of effective targeted agents. Although covalent KRAS^G12C inhibitorsi such as sotorasib and adagrasib have demonstrated clinical activity, pooled analyses indicate only modest response rates and short progression-free survival, with no effective options for non-G12C subtypes. This highlights the need for novel therapeutic strategies with broader efficacy and improved durability. We evaluated the antiproliferative effects of SP09, a novel benzoin-Schiff base derivative, in KRAS -mutant (A549, H460) and EGFR -mutant (PC9) NSCLC cells, as well as normal lung cells. Cell viability, colony formation, and cell cycle distribution were assessed, and the involvement of the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling axis was examined by western blot. SP09 selectively inhibited the proliferation of KRAS -mutant NSCLC cells (IC 50 ≈ 29 µM) with minimal toxicity to normal lung cells. Treatment induced G2/M arrest via downregulation of cyclin B1 and upregulation of p21. Mechanistically, SP09 activated the LKB1/AMPK pathway and suppressed mTOR signaling, leading to inhibition of downstream effectors, including P70S6K, S6, and sterol regulatory element-binding protein 1 (SREBP1). SP09 exerts potent and selective antiproliferative effects in KRAS -mutant NSCLC through dual regulation of cell cycle and metabolic signaling pathways. Given the restricted efficacy and rapid resistance associated with current KRAS -targeted therapies, our data highlight SP09 as a promising candidate for further preclinical development with potential translational value in KRAS -driven NSCLC.</p>","PeriodicalId":7969,"journal":{"name":"Anti-Cancer Drugs","volume":" ","pages":"137-145"},"PeriodicalIF":2.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12736418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}