Calreticulin (CALR) has been implicated in the genesis and progression of numerous tumors. Nevertheless, its impact on multiple myeloma (MM) remains ambiguous. This study aimed to explore the effect of CALR on the proliferation and drug sensitivity of MM cells and to delve into its underlying mechanism.

Ovarian cancer is the most lethal tumor in female reproductive system, which seriously threatens the life and health of women. Our previous study found that LAMC3 was down-regulated in ovarian cancer tissues and correlated with ovarian cancer resistance. However, the effects of LAMC3 interference on drug resistance in carboplatin-resistant ovarian cancer cells remain unknown. In the present study, the effects of LAMC3 interference on drug resistance, cell proliferation, cycle, apoptosis, and ultrastructure of carboplatin-resistant ovarian cancer cells were examined. The results showed that LAMC3 interference lowered drug resistance of carboplatin-resistant ovarian cancer cells. The cell proliferation was inhibited and cell apoptosis was promoted in carboplatin-resistant ovarian cancer cells with LAMC3 interference. Besides, LAMC3 interference arrested cell cycle and affected cell ultrastructure of carboplatin-resistant ovarian cancer cells. Furthermore, transcriptome sequencing and WB verification results revealed cell cycle, autophagy, ferroptosis, lysosome related key pathway proteins may be involved in LAMC3 interference regulating drug resistance of carboplatin-resistant ovarian cancer cells. This study indicated LAMC3 interference reduced drug resistance of carboplatin-resistant ovarian cancer cells principal by affecting cell cycle, autophagy, ferroptosis, and lysosome. The present study provides a potential target for clinical treatment of drug resistance in ovarian cancer.

Cholangiocarcinoma (CCA) is a prevalent bile duct cancer with limited treatment options. Cisplatin-based chemotherapy is a common approach, but response rates vary. Recently, chromosome aberrations have emerged as predictors of chemotherapy response in various malignancies. This study aimed to identify chromosomal aberrations associated with cisplatin response in CCA. A histoculture drug response assay was conducted on 20 fresh CCA tissues to determine cisplatin sensitivity. In parallel, chromosome aberration analysis was performed using chromosome microarray. Using chromosome microarray analysis on 20 CCA samples, we found distinct chromosomal aberration patterns between cisplatin responders and non-responders. Gains in 18q and 20q, and losses in 1p and 8p were more common in non-responders. Conversely, the responders exhibited gains in 8q and losses in 16q. Our heatmap analysis of log-2 ratio demonstrated difference in various chromosomes including 2, 3p, 5q, 6q, 7, 9p, 11q, 14q, 15q, 18q, 20q, and 22q between the response and the non-response to cisplatin. Further analysis using machine learning with random forest model identified genes like NCOA3, TPK1, CEP57L1, DEPDC5, and PLXNA4 as potential predictors of cisplatin response. Validation in a separate cohort of 33 CCA samples confirmed the association of NCOA3 and DEPDC5 with cisplatin response. Our findings suggest that chromosomal aberrations and specific genes may predict cisplatin response in CCA, potentially guiding personalized treatment strategies.

Pancreatic cancer (PC) is a highly aggressive and fatal malignancy, primarily affecting older males. Curcumin, a potential anti-cancer agent, has been shown to regulate key molecules in cancer progression, but its specific mechanisms in PC remain unclear. We conducted a comprehensive database search to identify curcumin-related targets in PC. Gene expression and immune correlations were analyzed using the GEO database, identifying differentially expressed hub genes (DEHGs). A method involving machine learning was employed to identify feature genes and create a nomogram, using external datasets and molecular docking for preliminary validation. Consensus clustering and subgroup comparisons were also performed based on DEHGs expression. We identified 35 DEHGs strongly associated with immune cell infiltration. Five feature genes (VIM, CTNNB1, CASP9, AREG, HIF1A) were used to build a nomogram, with the classification model showing AUC values above 0.9 in both training and validation groups. Molecular docking highlighted potential binding sites of five feature genes for curcumin. Clustering analysis categorized PC samples into four distinct subgroups: C1 and CII, which showed high expression and elevated immune cell infiltration, and C2 and CI, which exhibited the opposite pattern. Significant variations in scores of DEHG were seen between C1 and C2, in addition to between CI and CII. Curcumin may target DEHGs to influence PC, regulating immune and tumor proliferation mechanisms. These outcomes provide potential insights for medical applications and upcoming research.

A novel quinazoline-containing 1,2,3-triazole (4-TCPA) was synthesized to target VEGFR2 signaling for cancer treatment. Although current VEGFR2 inhibitors exhibit strong anticancer activity, their clinical use is limited due to severe side effects. Structural analysis of effective VEGFR2 inhibitors guided the design of 4-TCPA, ensuring the retention of Erlotinib's essential pharmacophoric features for optimal receptor binding. The compound was tested for its anticancer efficacy against A549 (lung cancer), MCF7 (breast cancer), K562 (leukemia), and human normal fibroblast HFF2 cells. 4-TCPA demonstrated inhibitory activity in nearly all assays, with IC50 concentrations of 35.70 μM for A549, 19.50 μM for MCF7, 5.95 μM for K562, and 135.2 μM for HFF2. Further in vitro biological evaluations examined its mechanistic impact on EGFR, mTOR, Akt, MAPK, and PIK3CA. Apoptotic activity was assessed through Annexin V/PI double staining and caspase-3/7 activation, confirming its ability to induce both early and late apoptosis. Additionally, real-time quantitative PCR (qRT-PCR) was conducted to evaluate the expression levels of Akt, mTOR, MAPK, PIK3CA, EGFR, and VEGFR2. Results showed that 4-TCPA down-regulates these targets in a time-dependent manner, triggering apoptosis across all tested cancer cell lines. The study suggests that 4-TCPA may serve as a promising anticancer agent due to its targeted VEGFR2 inhibition and apoptotic induction, warranting further investigation. These findings support the potential of 4-TCPA as an effective treatment strategy for various cancers.

Immunotherapy has revolutionized cancer treatment by leveraging the body's immune system to combat malignancies. However, on-target, off-tumour (OTOT) toxicity poses significant challenges, often leading to the failure of clinical trials for the development of immunotherapeutic drugs. The molecular engineering of clinically relevant, tumour-selective prodrugs, activated in a targeted way, could help minimize systemic toxicity while maximizing anti-tumour efficacy. Here, we propose a Single Atom Engineering for Radiotherapy-Activated Prodrug (SAE-RAP) technique for the development of radiotherapy-activatable small-molecule immune agonist prodrugs. We show that introducing a single oxygen atom into the TLR7/8 agonist R848 significantly reduces the EC50 value by over 4000-fold, hence mitigating severe side effects following systemic administration. In preclinical tumour mouse models, exposure to radiotherapy removes the protective mask provided by the oxygen atom and locally rescues the activity of the prodrugs, triggering anti-tumour immunity and limiting the growth of primary and distal tumours. The SAE-RAP technique may be further utilized for developing radiotherapy-activated prodrugs for next-generation combination therapies that transcend traditional limitations.

Basal cell carcinoma (BCC) is the most common cancer in the world, and its incidence continues to rise. Known risk factors for BCC include chronic UV exposure, advanced age, and genetic predisposition. A large majority of BCC cases have an altered Hedgehog (Hh) signaling pathway. When a large BCC develops on the face, it can pose unique treatment challenges due to functional and cosmetic considerations-even with Mohs micrographic surgery (MMS). Traditional treatment options may be limited, prompting the use of targeted therapies such as vismodegib for unresectable cases. Vismodegib, an Hh inhibitor, is approved by the US Food and Drug Administration for treatment of locally advanced or metastatic BCC. This case report details the successful management of a large BCC on the nose of an elderly patient using vismodegib.

Recently, essential oils (EOs) have garnered attention for their biological properties as a source of natural compounds with anticancer, antibacterial, and antioxidant effects. Chiliadenus iphionoides (Boiss.& Blanche) Brullo is a fragrant aromatic species indigenous to Palestine and the neighboring countries. It is utilized by the Bedouins for the treatment of many ailments. This study aimed to analyze the chemical composition of essential oil extracted from the desiccated leaves of Chiliadenus iphionoides (Boiss.& Blanche) Brullo and to assess its in vitro antioxidant, anticancer, and α-amylase and lipase inhibitory activities. The EO obtained during hydrodistillation was analyzed using gas chromatography-mass spectrometry to ascertain their chemical composition. GC-MS analysis of the EO from dried Chiliadenus iphionoides (Boiss.& Blanche) Brullo leaves identified 47 compounds, comprising 98.81% of the total oil. The predominant constituents included cresol methyl ether (52.93%), ethyl 2-octynoate (14.36%), epi-α-cadinol (6.56%), 1,8-cineole (4.25%), and 7-epi-α-eudesmol (3.66%). The EO exhibited significant antioxidant activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) with an IC50 value of 19.83 ± 0.99 μg/mL. Nevertheless, it exhibited limited lipase activity and subpar α-amylase activity. Chiliadenus iphionoides (Boiss.& Blanche) Brullo EO exhibited significant cytotoxicity against B16F10 and MCF-7 cancer cell lines, with IC50 values of 8.74 ± 0.11 and 13.68 ± 0.17 μg/mL, respectively. The combination of the anticancer medication Taxol (10 ng) with Chiliadenus iphionoides (Boiss.& Blanche) Brullo EO at concentrations of 25 μg/mL and 50 μg/mL significantly enhanced the inhibitory efficacy of Taxol against MCF-7 and B16F10 cells.

Axitinib is a second-generation tyrosine kinase inhibitor that works by selectively inhibiting vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3). Through this mechanism of action, axitinib blocks angiogenesis, tumor growth and metastases and therefor it shows significant promise as a chemotherapeutic agent for various types of cancer. Nevertheless, the clinical efficacy of this substance is hindered by its restricted solubility in water and inadequate stability. To address these challenges, we developed spanlastics with polyethylene glycol (PEG) to improve the efficacy and stability of axitinib against breast and ovarian tumor malignancies in a targeted manner. Moreover, the study conducts a thorough examination of the interactions between the ligand Axitinib alone or after coating with PEG and a diverse array of protein types in breast (Dopamine, VEGFR) and ovarian cancer (EGFR, BCL-xL). The fabrication of axitinib- spanlastics was achieved through a thin-film hydration method. The evaluation of the impact of formulation factors on the features of nanovesicles was conducted using the I- optimal design. Subsequently, the optimum formulation was calculated. The optimal formulation was coated with polyethylene glycol (axitinib-PEG-spanlastics). An in vitro assessment was computed to evaluate the efficiency of the optimized axitinib-PEG-spanlastics against the MCF-7 breast cancer cell line and the OV-2774 ovarian cancer cell line. The optimized axitinib-PEG-spanlastics formulation exhibited a diameter of 563.42 ± 8.63 nm, accompanied by a zeta potential of -46.44 ± 0.09 mV. The formulation demonstrated an 84.32 ± 3.64% entrapment percent and a cumulative release of 73.58 ± 3.37% during a 4-hour period. The results obtained from the WST-1 assay showed a significant decrease in the percentage of cell survival, reaching 50% at a concentration of 0.68 µM for the PEG-spanlastics. In contrast, the axitinib free drug suspension exhibited 50% cell survival at a concentration of 1.1 µM in the breast cancer (MCF-7) cell line. In MCF-7 cells, the percentage of apoptotic cells generated by axitinib-PEG-spanlastics compared to the free drug suspension was 70.76 ± 4.971% vs. 32.6 ± 1.803%, while in OV-2774 cells, it was 43.55 ± 4.243% vs. 24.44 ± 4.950%. These results propose that Axitinib-PEG-spanlastics have the potential to be a successful nanoplatform for targeting breast and ovarian cancer and effectively managing tumors.

Immune checkpoint inhibitors (ICIs) have emerged as a highly effective treatment option for patients with metastatic melanoma. As not all patients respond to ICI immunotherapy, imaging biomarkers are required to accurately monitor early response to therapy. Therefore, the aim of this study was to evaluate contrast-enhanced ultrasound (CEUS) with VEGFR2-targeted microbubbles for monitoring the effects of combined anti-PD-L1/anti-CTLA-4 immunotherapy in a murine melanoma model.

This study aimed to investigate the efficacy of cyclocryotherapy applied at the 3 o'clock and 9 o'clock positions in combination with intravitreal anti-vascular endothelial growth factor (VEGF) injections in patients with advanced neovascular glaucoma (NVG).

To report real-life data of eyes with neovascular age-related macular degeneration (nAMD) treated with vascular endothelial growth factor (VEGF) inhibitors for an average of 10 years.

Small molecule inhibitors of lysine deacetylases (KDACs), exemplified by histone deacetylases (HDACs), exhibit significant promise as cancer therapeutics. Using a modular combinatorial chemistry approach, a novel class of KDAC inhibitors (KDACi) containing the aminophenyl-benzamide headgroup have been developed, which incorporate a vinyl group within the linker region for active site stabilisation and a trifluoromethyl moiety within the capping group to exploit enzyme surface topology. Consequently, a class I selective KDACi (7) with a preference towards HDAC1 over other class I KDACs was identified. This KDACi orientates differently within the KDAC active site and exhibits an improved antitumour profile relative to the benchmark class I selective KDACi Entinostat (1). The clinical potential of 7 is further exemplified by the inhibition of tumour growth in an in vivo model of ovarian cancer. These results offer significant scope for the rational development of KDACi with improved selectivity against specific KDAC and widespread therapeutic potential.

Triple-negative breast cancer (TNBC) represents the most malignant subtype of breast cancer. The clinical application of PARP inhibitors (PARPi) is limited by the low frequency of BRCA1/2 mutations in TNBC. Here, we identified that MTAP deletion sensitized genotoxic agents in our clinical cohort of metastatic TNBC. Further study demonstrated that MTAP deficiency or inhibition rendered TNBC susceptibility to chemotherapeutic agents, particularly PARPi. Mechanistically, targeting MTAP that synergized with PARPi by disrupting the METTL16-MAT2A axis involved in methionine metabolism and depleting in vivo s-adenosylmethionine (SAM) levels. Exhausted SAM in turn impaired PARPi-induced DNA damage repair through attenuation of MRE11 recruitment and end resection by diminishing MRE11 methylation. Notably, brain metastatic TNBC markedly benefited from a lower dose of PARPi and MTAP deficiency/inhibition synergy due to the inherently limited methionine environment in the brain. Collectively, our findings revealed a feed-forward loop between methionine metabolism and DNA repair through SAM, highlighting a therapeutic strategy of PARPi combined with MTAP deficiency/inhibition for TNBC.

Targeting the vascular endothelial growth factor (VEGF) pathway is crucial for antiangiogenesis therapy in treating cancers and diseases with abnormal blood vessel growth. Human umbilical vein endothelial cells (HUVECs) activated by VEGF are widely used for exploring the impact of antiangiogenic agents on cellular functions. In this study, seven quinolinone derivatives were successfully synthesized and structurally confirmed through 1H, 13C NMR, and HRMS spectra. Compounds 4 and 5 exhibited significant inhibition of VEGF-induced HUVEC proliferation, with IC50 values of 84.8 and 58.1 μM for 48 h. Compounds 3‒6 effectively suppressed VEGF-induced HUVEC migration and invasion, demonstrating potent inhibitory effects in the Matrigel tube formation assay. Compounds 4 and 5 directly bind to vascular endothelial growth factor receptor 2 (VEGFR2), thereby inhibiting VEGFR2-mediated downstream angiogenic signaling pathways (PI3K/Akt, ERK1/2/p38 MAPK, and FAK). Cell-cycle analysis revealed that compounds 4 and 5 induced substantial G2/M phase arrest in HUVECs, accompanied by increased p53 phosphorylation and upregulation of p21cip1 expression. Compounds 3‒6 also induced apoptosis in HUVECs, as evidenced by nuclear condensation, DNA laddering, and increased Annexin V/PI staining. Western blot analysis showed that compounds 4 and 5 significantly increased the levels of apoptosis-related proteins, particularly cleaved caspase-3 and PARP. Through in vivo experiments utilizing the chicken embryo chorioallantoic membrane (CAM) assay, a marked decline in newly formed microvessels was observed posttreatment with both compounds. These results suggest that compounds 4 and 5 show promise as antiangiogenic agents, warranting further investigation into their therapeutic efficacy in conditions characterized by abnormal angiogenesis.

A series of thiadiazole-based derivatives were synthesized and evaluated for their potential as VEGFR-2 inhibitors and anticancer agents. Among them, compound 7b demonstrated significant cytotoxic activity against MCF-7 breast cancer cells, with an IC50 value of 6.13 µM, surpassing that of the reference drug sorafenib (IC50: 7.26 µM). Compound 7b also exhibited potent VEGFR-2 inhibition with an IC50 of 40.65 nM, outperforming sorafenib (IC50: 53.32 nM). Further investigation into the mechanism of action revealed that compound 7b induced significant changes in the cell-cycle distribution of MCF-7 cells, causing G1 arrest and delaying progression through the G2/M phase. Apoptosis analysis demonstrated that compound 7b primarily induced late apoptosis (55.90%) and necrosis (21.81%), with only 22.26% of cells remaining viable. Treatment with 7b increased the expression of the proapoptotic gene BAX (4.19 ± 0.34-fold) and suppressed the expression of the antiapoptotic gene Bcl-2 (0.38 ± 0.02-fold), resulting in a dramatic increase in the BAX/Bcl-2 ratio (11.03 ± 1.66-fold). Additionally, caspase-8 and caspase-9 levels were elevated by 2.99 ± 0.22-fold and 4.13 ± 0.11-fold, respectively, confirming activation of both intrinsic and extrinsic apoptotic pathways. In conclusion, compound 7b is a potent VEGFR-2 inhibitor with promising anticancer activity, demonstrating cytotoxicity, inhibition of cell migration, and induction of apoptosis in MCF-7 cells. These results suggest that compound 7b has the potential to be developed as a therapeutic agent for breast cancer treatment, warranting further in vivo and mechanistic studies.

With the increasing use of programmed cell death protein 1 and programmed cell death ligand 1 (PD-1/PD-L1) inhibitors in cancer treatment, hyponatremia has emerged as a notable adverse event associated with this class of drugs.

Multi-drug resistance (MDR) in cancer significantly hinders effective treatment, leading to poor patient outcomes. The study investigates the potential of natural compounds, Alisol B 23-acetate (B23) and Alisol A 24-acetate (A24), to reverse MDR through various mechanisms on cancer cell membranes.

Lung cancer (LC) is one of the leading causes of cancer-related mortality globally, and despite numerous available treatment modalities, the 5-year survival rate for LC patients remains approximately 20%. A large proportion of LC patients are diagnosed at advanced stages, and conventional treatments frequently exhibit poor efficacy and are often associated with numerous side effects. Therefore, there is an urgent need for innovative therapeutic strategies to meet the needs of LC patients. Recent advances in nanotechnology have opened new avenues for the diagnosis and treatment of LC, particularly through the use of nanoparticles (NPs) as a drug delivery system, which offer enhanced therapeutic potential. Due to their unique physicochemical properties, NPs are widely employed in LC drug delivery systems. They can efficiently load pharmaceuticals and specifically target cancer cells to enhance diagnostics and treatment. Additionally, NPs can encapsulate multiple therapeutic agents, including targeted molecules and photosensitive reagents. Despite the substantial promise of nanotechnology in LC treatment, several challenges remain in its clinical application. This review represents a comprehensive overview of LC, encompassing risk factors, types, stages, mechanisms, and traditional treatment strategies. Furthermore, we thoroughly emphasized the current nanotechnology-based diagnostics and therapies for LC. In summary, the ongoing advancement of drug delivery systems highlights the potential of nanotechnology to enhance traditional LC treatments and facilitate the development of new therapeutic strategies. Future research will focus on optimizing the unique properties of various NPs to enhance treatment outcomes and offer personalized therapeutic strategies, ultimately improving the prognosis and quality of life for LC patients.

Aggressive natural killer cell leukaemia (ANKL) is a rare form of NK cell lymphoma with a very low incidence and poor prognosis. While multi-agent chemotherapy including L-asparaginase has been used to treat ANKL patients, they often cannot receive adequate chemotherapy at diagnosis due to liver dysfunction. PPMX-T003, a fully human monoclonal antibody targeting the transferrin receptor 1, shows promise in treating ANKL by helping patients recover from fulminant clinical conditions, potentially enabling a transition to chemotherapy. This study aimed to evaluate the tolerability, safety, efficacy, and pharmacokinetics of repeated continuous intravenous PPMX-T003 in patients with ANKL.