Cancer remains one of the leading causes of death globally, presenting significant challenges to healthcare systems due to its complexity and the limitations of current therapeutic strategies. Despite advancements in anticancer drug development, monotherapies often fail to provide long-term efficacy due to the emergence of drug resistance. This resistance is primarily due to the activation of compensatory pathways in cancer cells, which allows them to bypass the effects of single-target therapies. To overcome this, targeting multiple key proteins simultaneously has emerged as a promising strategy to enhance therapeutic outcomes and address resistance mechanisms. In this study, 2-Phenylindole derivatives were explored as MCF7 breast cancer cell line inhibitors using 3D-QSAR modeling to design more effective compounds. The CoMSIA/ SEHDA model demonstrated high reliability (R² = 0.967) and a strong Leave-One-Out cross-validation coefficient (Q² = 0.814), further validated by external testing (R²Pred = 0.722). Six new compounds with potent inhibitory activity were designed, and their favorable ADMET profiles were confirmed. Molecular docking studies revealed that the newly designed compounds exhibited better binding affinities (-7.2 to -9.8 kcal/mol) to key cancer-related targets (CDK2, EGFR, and Tubulin) compared to the reference drug and the most active molecule (molecule 39) in the dataset. Additionally, 100 ns molecular dynamics simulations confirmed the stability of the best-docked complexes, highlighting their potential as promising candidates for anticancer drug development.

Cisplatin is a widely used chemotherapeutic drug for various cancers. One of the common adverse effects of cisplatin is nephrotoxicity including acute kidney injury (AKI) and acute kidney disease (AKD). Single Nucleotide Polymorphisms (SNPs) can be used to identify cancer patients who are susceptible to developing cisplatin-induced nephrotoxicity (CIN). In this study, we validated the association between 6 SNPs in the drug metabolizing enzyme genes, SLC22A2 (rs316019) & EPHX1 (rs1051740), and the DNA repair genes, ERCC1 (rs11615 & rs3212986) & ERCC2 (rs13181 & rs1799793), and CIN in the 169 Thai patients with head and neck, lung, or esophageal cancer. Effect of these SNPs on cumulative incidence of AKD, progression-free survival (PFS), and overall survival (OS) was also assessed. EPHX1 rs1051740 TC genotype was significantly associated with AKD in co-dominant [OR 2.894, 95% CI 1.091-7.680; P = 0.033] and over-dominant [OR 2.793, 95% CI 1.333-5.851; P = 0.006] models, and with an increased cumulative incidence of AKD (P = 0.021). Additionally, ERCC2 rs13181 and rs1799793 were significantly associated with OS (P = 0.002 and 0.004). Our results reveal an association between EPHX1 rs1051740 and AKD, and confirms the previously reported associations between ERCC2 SNPs and OS. These findings may help in predicting CIN in Thai cancer patients.

Breakpoint cluster region::Abelson 1 (BCR::ABL1) tyrosine kinase inhibitors (TKIs), such as imatinib, are used to treat chronic myeloid leukemia (CML), but BCR::ABL1 TKI resistance develops in 20-30% of affected patients, which poses a serious clinical problem. MicroRNAs (miRNAs) have been related to the development and aggravation of CML and BCR::ABL1 TKI resistance; however, the underlying mechanisms remain unknown. In this study, we explored the roles of miRNAs in imatinib resistance as well as the underlying mechanism in imatinib-resistant K562 (K562/IR) cells. Gene amplification was analyzed using array comparative genomic hybridization. Cell survival was confirmed by trypan blue dye staining assay. Expression of protein and miRNA was assessed using western blotting and real-time polymerase chain reaction (PCR). We found that miR-29a, miR-29b, miR-592, miR-595, miR-671, miR-3666, and miR-3907 were upregulated. Real-time PCR confirmed increased expression of miR-29a and miR-29b in K562/IR cells. Additionally, miR-29a and miR-29b mimics reduced imatinib sensitivity in K562 cells. We also found that miR-29a and miR-29b inhibitors partially overcame imatinib resistance in K562/IR cells. Furthermore, miR-29a and miR-29b mimics enhanced extracellular signal-regulated kinase (ERK) 1/2 activity by decreasing neurofibromin 1 (NF1) expression in K562 cells, whereas miR-29a and miR-29b inhibitors reduced ERK1/2 activation by increasing NF1 expression in K562/IR cells. These findings indicated that miR-29a and miR-29b are involved in imatinib resistance by downregulating NF1 expression and activating ERK1/2. Additionally, the miR-29a, miR-29b, and NF1/ERK axis may be potential targets for the treatment of imatinib-resistant CML.

Pinostrobin (PIN), a natural flavonoid found in Boesenbergia rotunda, Alpinia zerumbet, and other botanicals, has shown promising anticancer potential due to its multitargeted mechanisms and favorable safety profile. This review consolidates current evidence on PIN's anticancer properties, focusing on its molecular mechanisms, pharmacokinetics (PKs), and therapeutic potential. A systematic literature search was conducted using PubMed, Scopus, ScienceDirect, and Google Scholar to identify preclinical studies on PIN's bioactivity, PK, and toxicity. PIN exerts potent anticancer effects by inducing ROS-mediated apoptosis, cell cycle arrest via p21 upregulation and cyclin D1 suppression, and reducing proliferation and inducing cytotoxicity. It also inhibits metastasis by targeting migration, adhesion, and angiogenesis. PK data reveal good intestinal absorption and metabolic transformation primarily, although limited solubility and brain penetration remain challenges. Toxicity studies show no adverse effects at therapeutic doses (≤ 100 mg/kg), with selective cytotoxicity against cancer cells and protective antioxidant effects in normal tissues. Beyond oncology, PIN also exhibits several pharmacological properties. PIN's ability to target key cancer pathways, along with its low toxicity and broad pharmacological potential, makes it a strong candidate for adjuvant therapy. The novelty of this study is its integrated analysis of PIN's anticancer mechanisms, PK, and safety, along with proposed strategies to bridge the gap toward clinical application. Clinical trials remain essential to confirm its efficacy.

PurposeTo comprehensively evaluate the efficacy and safety of combining poly (ADP-ribose) polymerase (PARP) inhibitors with chemotherapy in patients with advanced breast cancer.MethodsA systematic literature search was conducted in PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov to identify randomized controlled trials (RCTs) evaluating PARP inhibitor-chemotherapy combinations. Studies reporting progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety outcomes were included. Data extraction and quality assessment were performed independently by two reviewers, and a meta-analysis was conducted using random-effects models.ResultsOf 970 studies retrieved, four RCTs involving 1064 patients met the inclusion criteria. PARP inhibitors combined with chemotherapy significantly improved PFS (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.63-0.84, P < .0001) and showed a trend towards improved OS (HR 0.93, 95% CI 0.79-1.09, P = .36), though this was not statistically significant. There was no significant improvement in ORR (RR 1.08, 95% CI 0.98-1.20, P = .13). Regarding safety, no significant difference was observed in all grades or grade 3-4 adverse events (AEs) overall, but the combination therapy was associated with an increased risk of anemia, nausea, and diarrhea (RRs ranging from 1.14 to 1.29, all P < .01).ConclusionPARP inhibitor combined with chemotherapy is an effective option for the treatment of patients with advanced breast cancer, but its potential increased risks of specific AEs need to be weighed. Clinicians should make individualized treatment plans according to the specific conditions of patients, comprehensive consideration of efficacy and safety.

Hepatocellular carcinoma (HCC) most prevalent form of liver cancer and poses a few available treatments and is a major worldwide health burden. Monacolin X, a natural compound derived from the marine sponge-associated symbiont Monascus ruber, has garnered attention for its potential anticancer and anti-angiogenesis properties. This current study aimed to investigate the anticancer and apoptosis-inducing effects of Monacolin X against the human liver cancer (HepG2) cell line in vitro. This present study utilized various assays to assess cytotoxicity by MTT assay, apoptosis induction, DCFH-DA staining to measure the intracellular ROS levels, and apoptosis-and inflammation-related gene expression changes induced by the Monacolin X. The MTT results discovered dose-dependent cytotoxicity in HepG2 cells with an IC50 value of 72.4 μM. The apoptosis-inducing effect of Monacolin X was evident through propidium iodide (PI) and acridine orange/ethidium bromide (AO/EB) staining, accompanied by increased intracellular ROS levels and downregulated expression of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and modulation of key apoptosis regulators (Bax and Bcl-2) as determined by qPCR analysis. In conclusion, these observations suggest a mechanism whereby Monacolin X has potent anticancer activity against the HepG2 cell line, and further investigation will be required to determine the molecular pathways responsible for the potential therapeutic effects for the clinical implications in liver cancer.

BRAF is a proto oncogene that functions as a key signal transducer in the MAPK-ERK pathway, which regulates cell growth, division, and survival. Mutations in BRAF, particularly the V600E substitution in its kinase domain, are major drivers in melanoma and several other metastatic cancers, including breast, colorectal, NSCLC, and gastrointestinal cancers. In this study, novel inhibitors targeting the BRAF(V600E) mutant using a structure-based drug design approach are identified. Four chemical libraries ChemDiv Kinase, ChemDiv Anticancer, NCI, and ChEMBL Kinase SARfari are screened. Compounds from the ChemDiv Anticancer database show better Glide scores comparable to the FDA-approved BRAF inhibitor Vemurafenib. The compounds P184-1419 and P184-1479 score -12.688 and -12.012 kcal/mol, respectively, versus -14.288 kcal/mol for Vemurafenib. Top hits are further validated using GOLD docking, X-score ranking, and interaction profiling via LigPlot. Molecular dynamics simulations, principal component analysis, and free energy calculations confirm the stability of protein-ligand complexes. Biolayer interferometry assays reveal P184-1419 exhibits stronger binding affinity (KD = 151 μM) than Vemurafenib (KD = 437 μM). These findings suggest P184-1419 is a promising lead compound against BRAF(V600E), offering potential for future development of more effective cancer therapies.

Envafolimab is a novel immune checkpoint inhibitor (ICI) with several advantages due to its subcutaneous administration. Phases I and II randomized controlled trials have demonstrated promising efficacy in treating colorectal and gastric cancer. However, the safety and efficacy of Envafolimab in patients with advanced lung cancer remain to be investigated.

Breast cancer as a "cold" tumor presents an immunosuppressive microenvironment and inferior T-lymphocyte infiltration, leading to poor efficacy of immune checkpoint blockade (ICB) therapies. It is urgent to develop new effective combination treatment strategies. Pyroptosis is an inflammatory form of programmed cell death mediated by Caspase-1/GSDMD pathway, which can cause immunogenic cell death (ICD) and boost the immunogenicity of tumor. In this study, an immune activator (siRNAPD-L1@HA-ZIF-8) was proposed based on metal-organic framework (ZIF-8) nanosystem carrying Zn2+ and PD-L1 siRNA to improve anti-tumor immunotherapy through evoking pyroptosis combined with immune checkpoint blockade. We found that siRNAPD-L1@HA-ZIF-8 could disintegrate under low pH and release massive amounts of Zn2+, leading to elevated intracellular osmolarity and ROS, eventually resulting in pyroptosis. Zn2+ overload-triggered pyroptosis caused ICD effect and promoted the maturation of dendritic cells and infiltration of T-lymphocytes, which reprogramed the immunoecology of tumor from "cold" to "hot" state. Meanwhile, the co-delivered PD-L1 siRNA decreased the expression of PD-L1 protein on the tumor surface, relieving immune evasion and recovering the recognition and killing ability of cytotoxic T-lymphocytes, further boosting the immune response. This research not only confirmed the potential of ZIF-8 intrinsically as an immune activator that induces pyroptosis in combination with encapsulated PD-L1 siRNA-mediated ICB therapy for the first time, but also adequately revealed the immune responses mechanism by multiple techniques. This study will provide new strategies for pyroptosis-mediated treatments for augmented anti-tumor immunotherapy and greatly inspire the further development of immune activators based on Zn2+ overload-triggered pyroptotic pathway.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have become key agents in the treatment of hormone receptor positive (HR +), human epidermal factor receptor 2 negative (HER2-) metastatic breast cancer (MBC). In combination with endocrine therapy, CDK4/6 inhibitors are currently considered first-line treatment for HR + /HER2- MBC. There are three CDK4/6 inhibitors currently available: palbociclib, ribociclib and abemaciclib. The toxicity profiles of the CDK4/6 inhibitors are well-detailed in the respective clinical trials and post-marketing reports. This review will detail the hepatotoxic effects of CDK 4/6 inhibitors and how the incidence rate compares among agents.

This study investigated the protective effects of verbascoside (VER) against 5-fluorouracil (5-FU)-induced gastrointestinal mucositis in Wistar albino rats.

Cancer remains one of the most deadly diseases in the world, requiring constant growth and improvements in therapeutic strategies. Traditional cancer treatments, such as chemotherapy, radiotherapy, and surgery, have limitations like off-target release, toxicity, and inefficient drug delivery. This study explains the role of bioinformatics and AI in optimizing and analyzing liposomal formulations for innovative and better cancer therapy. Molecular docking (MD), molecular dynamics simulations, and machine learning models are the computational techniques that can help to design stable liposomal carriers for drugs, predict receptor-ligand interactions, and can improve drug release efficiency. Improved liposome nanoparticles (LNPs) surface functionalization, the discovery of tumor-specific biomarkers, and the improvement of receptor-ligand interactions for accurate drug targeting are all made possible by bioinformatics tools and methodologies. Moreover, AI-assisted predictions and in silico modeling can speed up drug discovery and processing while eliminating the experimental expenditures and time. In the present review, we conducted MD studies to complement the discussed literature. MD was performed between cyclic RGD peptides (liposomal ligands) and the GPR116 receptor in triple-negative breast cancer, and between folic acid (liposomal ligand) and the Axl tyrosine kinase receptor for lung cancer, revealing strong and stable interactions and highlighting the amino acid residues involved. Notwithstanding current obstacles, computational tools have shown notable progress in nanomedicine, exploring more options for more individualized and effective cancer therapies. The combination of AI, machine learning, and multi-omics techniques to improve therapeutic efficacy and reduce side effects is a substantial key to the future of LNP-based cancer treatment.

To evaluate the performance and consistency of large language models (LLMs) across brand and generic oncology drug names in various clinical tasks, addressing concerns about potential fluctuations in LLM performance because of subtle phrasing differences that could affect patient care.

Digestive system cancers, including esophageal, gastric, colorectal, pancreatic, hepatocellular, and biliary tract cancers, constitute a major global health challenge. Despite therapeutic advancements, prognosis remains poor, highlighting the urgent need for novel treatment strategies. We hypothesized that drug repositioning, facilitated by pan-cancer analyses, could lead to the identification of effective treatment strategies for these cancers.

Basal cell carcinoma (BCC) is a prevalent form of skin cancer that can be localized or metastatic. Current evidence supports the use of Hedgehog (Hh) pathway inhibitors for locally advanced or metastatic BCC with resistance due to genetic alterations in the Hh pathway. This systematic review evaluated the prevalence of genetic alterations in Hh pathway genes in BCC.

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and remains a major contributor to global cancer-related deaths. The progression of HCC is strongly influenced by the dysregulation of the mechanistic target of rapamycin (mTOR) signaling pathway and impaired apoptotic mechanisms, particularly due to caspase-3 suppression. These molecular aberrations promote oncogenic proliferation and confer resistance to conventional therapeutic regimens. Existing treatment modalities are frequently constrained by limited efficacy, the emergence of drug resistance, and dose-limiting toxicities, highlighting the critical need for innovative and targeted therapeutic approaches to improve patient outcomes. This study investigates the dual anticancer mechanisms of formononetin, a bioactive isoflavone, focusing on its ability to suppress the mTOR signaling pathway and induce caspase-3 activation in hepatocellular carcinoma (HCC). By targeting these critical molecular pathways, formononetin exhibits therapeutic potential by impeding tumor progression and counteracting apoptosis resistance in HCC. In silico analyses employing molecular docking, PASS Online, and ProTox 3.0 were utilized to predict formononetin's biological activity, pharmacokinetic properties, and toxicity profile. These computational tools provided valuable insights into formononetin's potential therapeutic properties. To validate these predictions, in vitro studies were conducted, including cytotoxicity assays (MTT), apoptosis quantification via Annexin V-FITC/PI staining, and protein expression analysis of mTOR and caspase-3 using flow cytometry. The experimental results substantiated formononetin's capacity to suppress mTOR signaling and induce apoptotic cell death in HCC models. In silico analyses demonstrated that formononetin exhibited high binding affinities to mTOR (- 8.7 kcal/mol) and caspase-3 (- 7.2 kcal/mol), supported by favorable pharmacokinetic properties and low toxicity profiles. Cytotoxicity assays revealed selective activity against HepG2 cells, with an IC50 of 10.397 µg/mL, while showing minimal effects on normal Vero cells. Flow cytometry confirmed a dose-dependent induction of apoptosis, evidenced by a significant increase in caspase-3 expression and a corresponding decrease in mTOR levels at a concentration of 10.397 µg/mL (p < 0.01). Formononetin exhibits a dual mechanism of therapeutic action, simultaneously suppressing mTOR signaling and activating caspase-3-mediated apoptosis, thereby representing a promising targeted strategy for HCC intervention. Further, preclinical in vivo validation and clinical investigations are required to confirm these mechanistic findings and evaluate translational potential.

The most common cancer in women worldwide and an important contributor to cancer-related death is breast cancer. Despite advances in treatment, current therapeutic methods remain insufficient, necessitating the development of innovative approaches. Nanotechnology, particularly silver nanoparticles (AgNPs), has emerged as a promising avenue in cancer therapy, offering the ability to target cancer cells through multiple mechanisms. In the current study, we aimed to investigate the anticancer potential of curcumin-biosynthesized AgNPs (C-AgNPs) and their molecular mechanisms on MCF-7 breast cancer cells. Cytotoxicity was assessed using the MTT assay, and the anti-migratory effect was determined through the scratch assay. The molecular mechanisms underlying these effects were investigated using RT-PCR to measure the expression levels of apoptotic-related genes, including P53, BAX, P21, and Bcl-2. Our results showed that C-AgNPs significantly inhibited MCF-7 cell migration. Moreover, gene expression analysis indicated the induction of apoptosis by upregulation of pro-apoptotic genes BAX and P53 and downregulation of Bcl-2. C-AgNPs demonstrated potent cytotoxic and anti-metastatic effects on MCF-7 cells, with the ability to induce apoptosis. C-AgNPs represent a promising candidate for the development of novel breast cancer therapies. However, further research is needed to address this effectiveness.

Improved treatment strategies for HPV-positive cancers are urgently required. The viral E6/E7 oncoproteins are essential for the proliferation of HPV-positive cancer cells and considered attractive therapeutic targets. Metformin is proposed to be repurposed for cancer therapy, but this is under controversial debate. We previously demonstrated that E6/E7 expression and the proliferation of HPV-positive cancer cells are repressed by Metformin. Here, we explore the effects of Metformin on the phenotype of HPV-positive cancer cells in detail, either applied as monotreatment or in combination with chemotherapeutic agents. We provide evidence that the downregulation of E6/E7 is not the primary mechanism underlying Metformin's growth-inhibitory effect in HPV-positive cancer cells. Specifically, compared to targeted E6/E7 repression by RNA interference (RNAi), Metformin treatment differently altered the expression of growth regulatory proteins, exerted different effects on the cell cycle, and was able to suppress growth even in the presence of E6/E7. Furthermore, we found that cancer cells pre-treated with Metformin become resistant to senescence induction by the pro-senescent chemotherapeutic agent Etoposide, likely as a secondary effect of Metformin-induced growth inhibition. Finally, depending on experimental conditions, we uncover divergent, even opposing, effects on the proliferation of HPV-positive cancer cells when Metformin is combined with Cisplatin, with p53 playing a key role in these processes. Collectively, our results show that Metformin exerts complex effects on the phenotype of HPV-positive cancer cells, which are critically influenced by experimental conditions. Our findings may also explain the discrepant results in the literature, reporting agonistic or antagonistic effects upon combining Metformin with Cisplatin.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the effectiveness and safety of immune checkpoint inhibitors (ICIs) for people with advanced, unresectable or metastatic oesophageal cancer.

Could the next major advancement in cancer therapy stem from utilizing the body's own cells to precisely deliver potent anti-cancer agents directly to tumors? This innovative strategy, known as cell-drug conjugates (CDCs), represents a transformative approach to targeted cancer treatment by leveraging the inherent biological properties of cells. Leveraging the inherent biological properties of cells, these conjugates enable highly specific drug delivery and enhance therapeutic efficacy. Through mechanisms such as chemotaxis and immune evasion, CDCs can transport anticancer agents across biological barriers and selectively accumulate within the tumor microenvironment, facilitating precision therapy. Various cell types, including red blood cells, stem cells, and immune cells, serve as potential carriers in these systems, each possessing unique biological characteristics and antitumor ability. At present, there are few reviews on the preparation and function of CDCs in cancer therapy. This review systematically explores CDC applications in cancer therapy, including targeting mechanisms, fabrication strategies,in vivopharmacology, and clinical advancements. Furthermore, the review examines the technical challenges associated with this innovative drug delivery and therapeutic strategy, while also evaluating its potential for clinical translation.