Anti-cancer agents in medicinal chemistry最新文献

Introduction: Prostate cancer (PRAD) remains a leading malignancy with limited prognostic biomarkers and therapeutic targets. PRR22, a proline-rich protein-coding gene, has a role in PRAD that remains undefined. This study is the first to systematically investigate the clinical relevance and mechanistic implications of PRR22 in PRAD.

Methods: PRR22 expression was analyzed in TCGA-PRAD (n = 501), GSE55945, and the Human Protein Atlas datasets. Prognostic value was assessed via Kaplan-Meier and multivariate Cox analyses. Mechanistic insights were derived from GSEA, immune infiltration profiling, MSI/mRNA-si correlations, and drug sensitivity analysis. Experimental validation was performed via qRT-PCR in PRAD cell lines.

Results: PRR22 was significantly upregulated in PRAD tissues compared to normal tissues (p < 0.001) and independently predicted shorter progression-free survival (HR = 1.82, p = 0.009). Novel associations were identified between PRR22 and TGF-β signaling, immune evasion (e.g., LAG3 upregulation), microsatellite instability (MSI), and stemness (mRNA-si). High PRR22 correlated with resistance to multiple drugs (e.g., bicalutamide, vorinostat).

Discussion: PRR22 overexpression in PRAD is linked to poor prognosis and immune regulation, suggesting its potential as a prognostic biomarker and therapeutic target. Future research should focus on clinical validation and on exploring the molecular mechanisms underlying PRR22's role in PRAD.

Conclusion: PRR22 is a novel, independent prognostic biomarker and actionable therapeutic target in PRAD, linking tumor aggressiveness to immune microenvironment remodeling and drug resistance. These findings establish PRR22 as a candidate for clinical implementation in risk stratification and targeted therapy.

Introduction: Recent advancements in nanomedicine have drawn attention to the use of zinc oxide nanoparticles as apoptotic agents to address triple-negative breast cancer. Halophila beccarii-mediated zinc oxide nanoparticles (Hb-ZnONPs) were fabricated using zinc acetate dihydrate as the precursor.

Methods: The fabricated nanoparticles were characterized based on morphological, structural, and elemental composition using SEM and XRD. The antiproliferative potential of Hb-ZnONPs was studied using the BT-549 cell line as an in vitro model, employing the MTT assay and Annexin V-FITC/PI-based flow cytometry analysis.

Results: The Hb-ZnONPs exhibited characteristic absorption maxima at 367 nm with a particle size of 35 nm and -44.7 mV stability. XRD confirmed the hexagonal wurtzite structure with an elemental composition of 62.3% Zn and 25.79% Oxygen. The Hb-ZnONPs demonstrated significant cytotoxicity against BT-549 cells, with 35.26% apoptosis at 5 μg/ml and 38.25% apoptosis at 10 μg/ml. However, cells in the late apoptosis stage increased from 14.48% at 5 μg/ml to 28.16% at 10 μg/ml, indicating a nearly twofold increase with the higher concentration.

Conclusion: Hb-ZnONPs may act as promising apoptotic inducers in the chemotherapy of breast cancer.

Introduction: Rosmarinic acid (RA) is a phenolic acid known for its important biological activities. Although it has been shown to inhibit various cancer cell types, its effects on the suppression and induction of apoptosis in neuroblastoma cells remain unclear. In this study, the antiproliferation and apoptosis-inducing effects of various concentrations of rosmarinic acid on neuroblastoma cells (SH-SY5Y) were investigated. Additionally, molecular docking analysis was conducted to examine the interaction between rosmarinic acid and the antiapoptotic protein BCL2.

Methods: SH-SY5Y cells were treated with rosmarinic acid at concentrations of 50, 100, 150, and 200 μg/ml for 24 hours. The percentages of apoptotic and necrotic cells in cultures treated with the lowest and highest concentrations were assessed using the Annexin V/PI staining method. Furthermore, the interaction between rosmarinic acid and BCL2 protein was analyzed using molecular docking techniques.

Results: The viability of rosmarinic acid-treated SH-SY5Y cells decreased. In SH-SY5Y cells, the percentage of late apoptotic cells increased to 40%. Molecular docking results showed that the benzene ring of rosmarinic acid formed pi-alkyl interactions with PHE71 and van der Waals interactions with SER64, ALA72, SER75, and VAL115 of BCL2. The lowest binding energy was calculated as -7.2 kcal/mol.

Discussion: RA demonstrated a suppressive effect on SH-SY5Y cells by targeting the antiapoptotic protein BCL2, suggesting a potential mechanism of action through the induction of apoptosis.

Conclusion: RA inhibited neuroblastoma SH-SY5Y cell proliferation and induced apoptotic cell death. It inhibited the proliferation of neuroblastoma SH-SY5Y cells and promoted apoptotic cell death, potentially through interaction with the BCL2 protein.

Despite decades of research on promising new therapies, cancer remains a leading cause of morbidity and mortality. Over the years, extensive research has been conducted on the potential anticancer effects of various medicinal plants. One extremely promising agent or adjuvant that may be utilized for the prevention/ treatment of several malignancies is cedrol, a naturally occurring sesquiterpene. Cedrol modulates multiple molecular pathways involved in the protracted carcinogenesis process, including the generation of reactive oxygen species, activation of pro-death autophagy, inhibition of survival signals, promotion of apoptosis, and inhibition of minichromosome maintenance proteins. This review suggests that cedrol might be a unique medication for the treatment of glioblastoma, lung cancer, and colorectal cancers. Further in-depth investigations of cedrol's anticancer mechanisms are needed.

The challenging subtype of breast cancer known as Triple-Negative Breast Cancer (TNBC) is characterized by the absence of HER2 expression, progesterone receptors, and estrogen receptors. TNBC is linked to a harsh treatment trajectory, elevated rates of recurrence, and restricted therapeutic alternatives. The mainstay of treatment for TNBC has historically been conventional chemotherapy, especially taxanes like Docetaxel. However, the effectiveness of these drugs is frequently compromised by systemic toxicity and resistance mechanisms. The development of Nanosomal Docetaxel Lipid Suspension (NDLS) offers a promising alternative, designed to enhance Docetaxel's therapeutic index by improving solubility, reducing side effects, and optimizing tumor-targeted drug delivery. NDLS has potential as a delivery system for additional chemotherapy drugs or combination treatments. This study addresses the cellular and molecular causes of TNBC, emphasizes the drawbacks of traditional treatments, and offers a thorough examination of NDLS in preclinical and clinical settings. This review provides a thorough analysis of NDLS in TNBC, laying the groundwork for further studies and therapeutic applications.

Lin28 is a pivotal RNA-binding protein that regulates the biogenesis of let-7 microRNAs, which play a crucial role in the post-transcriptional regulation of oncogenes in cancer. The Lin28/let-7 axis is integral to the regulation of key cellular processes such as proliferation, differentiation, and apoptosis. Lin28 promotes the upregulation of oncogenes, including MYC, RAS, and HMGA2, by inhibiting the maturation of let-7, thereby facilitating tumor initiation, progression, and metastasis. Consequently, targeting the Lin28/let-7 interaction has emerged as a promising therapeutic strategy, particularly for malignancies that lack specific molecular targets. This approach holds potential for downregulating oncogene expression and inhibiting tumor progression. Through a comprehensive review of the literature, this article classifies Lin28/let-7 inhibitors into three categories: CSD/ZKD inhibitors, non-CSD/ZKD inhibitors, and let-7 restorers. CSD/ZKD inhibitors, such as TPEN and KCB3602, function by binding to the CSD or ZKD domains of Lin28, thereby inhibiting its activity. Non- CSD/ZKD inhibitors, including compounds like C1632 and Simvastatin, have been identified as molecules that can reduce Lin28 activity, though their binding sites remain unknown. Let-7 restorers, on the other hand, do not directly target Lin28 but instead work indirectly by modulating the activity of associated molecules, such as Zcchc11 and Zcchc6, thereby promoting the restoration of let-7 expression levels. Notable examples of these include IPA-3 and FPA124. This review summarizes recent advances in the development of Lin28/let-7 inhibitors and their therapeutic potential, providing an important reference for ongoing research on Lin28 inhibitors in cancer therapy.

Isocitrate Dehydrogenases (IDH) are ubiquitous enzymes essential for cellular metabolism, including the Krebs cycle, glutamine metabolism, lipogenesis, and redox balance. Mutations in IDH1 and IDH2 are implicated in several tumors - gliomas, Acute Myeloid Leukemia (AML), cholangiocarcinoma - altering enzyme activity and causing the overproduction of 2-hydroxyglutarate (2-HG). This oncometabolite disrupts α-KGdependent proteins, impairing key processes such as differentiation, division, and DNA repair. Understanding these genetic, biochemical, and clinical aspects has made IDH enzymes promising therapeutic targets, prompting the development of targeted inhibitors for tumors harboring IDH1 or IDH2 point mutations. Selective inhibitors like ivosidenib (AG-120) and enasidenib (AG-221), targeting mutant IDH1 and IDH2 respectively, block 2- HG production and induce differentiation, achieving clinical success - particularly in AML. However, resistance due to secondary mutations, especially in the allosteric binding site, remains a major obstacle. In response, novel approaches have emerged, such as covalent inhibitors like LY3410738, which irreversibly bind mutant residues, and dual inhibitors like vorasidenib (AG-881), which act on both IDH1 and IDH2 mutations and penetrate the blood-brain barrier for treating solid tumors. Still, many clinical factors must be considered. This review explores the current landscape of IDH-targeted therapies, emphasizing the need for novel inhibitors and highlighting innovative strategies, including the design of smaller, more potent molecules with favorable pharmacokinetics and the potential of drug repositioning. We underscore that discovering new antitumor compounds targeting IDH requires a collaborative effort across biomedical fields. These advancements aim to overcome resistance, broaden therapeutic options, and improve the effectiveness of IDH-targeted treatments.

Introduction: PTEN (Phosphatase and tensin homolog) is a valuable regulator of the PI3K-AKT and mTOR pathways and is frequently mutated in cancer-like glioblastoma. The WWPI HECT domain has a group of enzymes called E3 ligases that ubiquitinate and inactivate PTEN by binding to it, which ultimately inhibits its lipid phosphatase function and promotes nuclear delocalization. This investigation seeks to restore the PTEN tumor suppressive activity by inhibiting the WWPI HECT domain in-silico.

Methods: We virtually screened a library of ~960 compounds in the active pocket of the human WWPI HECT domain, and fifteen compounds were chosen based on their favorable binding affinities and highly negative docking scores.

Results: Among those hits, five compounds, C5, C6, C8, C9 and C11, properly fit the standard with favorable pharmacokinetic and drug-like quality. Their capacity to suppress cell propagation was evaluated in the U87 glioma cell line. The compounds (C5, C6, C8, C9 and C11) exhibited significant anti-proliferative capability with IC50 values of 6.98 ± 0.14 μM, 14.58 ± 1.49 μM, 11.12 ± 0.73 μM, 13.85 ± 1.63 μM and 18 ± 1.23 μM, respectively.

Discussion: Strong inhibitory action against glioma cells was shown by the discovered compounds, especially C5 and C8, suggesting that they may be able to restore PTEN tumor suppressive capabilities. A potential therapeutic intervention mechanism for glioblastoma is suggested by their interaction with the WWPI HECT domain.

Conclusion: This study has discovered novel inhibitors against the WWPI HECT domain, and a treatment option for glioblastoma.

PKM2 has emerged as a critical biomarker with the potential to enhance both diagnostic accuracy and therapeutic strategies in ovarian cancer. Due to its high fatality rate and difficulty identifying early signs, ovarian cancer remains a major global health concern. Biomarkers, particularly PKM2, provide targeted therapeutic methods and early detection. The complex role of PKM2 in cancer metabolism highlights its importance as a diagnostic biomarker, particularly through its involvement in the Warburg effect. Its interaction with key signaling pathways and tissue-specific expression patterns makes it a compelling target for personalized therapeutic strategies. Moreover, the detection of PKM2 in the blood of cancer patients further underscores its clinical utility and therapeutic relevance. Beyond diagnostics, PKM2 is also a promising therapeutic target. Preclinical research has reported that both activators and inhibitors of this protein are effective. For PKM2-based treatments to be successfully incorporated into clinical practice, extensive research and rigorous validation are required. To overcome the difficulties in managing ovarian cancer and accomplish the objective of improved early detection and individualised treatment methods, collaboration among the research, healthcare, and advocacy sectors is crucial. In conclusion, PKM2 represents a promising target in the fight against ovarian cancer, with the potential to improve diagnostic accuracy, therapeutic strategies, and overall patient survival.