Search Results (312)

Vascular smooth muscle cells (VSMCs), the contractile cells in the tunica media of blood vessels, maintain vascular tone. The proliferation of VSMCs is an important feature of vascular remodeling that contributes to the regulation of blood pressure. Autophagy, an intracellular self-degrading process that delivers cytoplasmic constituents to lysosomes, plays a vital role in VSMC proliferation. This is regulated by the dopaminergic and renin–angiotensin systems but their interplay in their regulation of autophagy in VSMCs is not well-understood. In rat VSMCs, fenoldopam (Fen), a dopamine D1-like receptor agonist, increased autophagy, as determined by the increase in the protein expressions of microtubule-associated protein 1 light chain (LC)3-II and beclin-1 (BECN1), in a time- and concentration-dependent manner. Conversely, angiotensin II (Ang II), the endogenous Ang II type 1 receptor (AT₁R) agonist, decreased the protein expression of LC3-II and BECN1, also in a time- and concentration-dependent manner. The production of cyclic adenosine monophosphate (cAMP) and autophagic LC3-II puncta in VSMCs were increased by Fen and decreased by Ang II. Pre-treatment of VSMCs with Rp-cAMPS, a protein kinase A inhibitor, prevented the Fen-mediated increase and the Ang II-mediated decrease in LC3-II protein expression. Fen decreased, whereas Ang II increased the phosphorylation of P70S6K, a direct downstream mammalian target of rapamycin (mTOR). The inhibitory effect of Fen and stimulatory effect of Ang II on P70S6K phosphorylation were prevented by Rp-cAMPS. Ang II also decreased the Fen-mediated increase in cAMP production, while Fen attenuated the Ang II-mediated increase in cell proliferation, a response that occurs downstream of autophagy. Moreover, Ang II prevented the Fen-mediated inhibition of cell proliferation, an effect that was blocked by losartan, an AT₁R antagonist. These results demonstrate that Fen and Ang II counter-regulate autophagy and proliferation of VSMCs via the mTOR pathway, which is cAMP-dependent. Full article

Collapsin Response Mediator Protein 2 (CRMP2) has emerged as a central node in the pathogenesis of chronic pain, functioning as a multimodal ‘molecular switch’ that regulates microtubule dynamics, ion channel trafficking, and synaptic plasticity. The dysregulation of CRMP2, particularly through aberrant post-translational modifications (PTMs) such as phosphorylation and SUMOylation, is a critical driver of both peripheral and central sensitization. This review systematically examines the structure, regulation, and multifaceted roles of CRMP2 in pain signaling pathways. We then critically evaluate a spectrum of CRMP2-targeted therapeutic strategies, including small-molecule inhibitors, peptide-based agents, and gene silencing, highlighting their promising preclinical efficacy and safety profiles. Despite challenges in targeting specificity and central nervous system delivery, we posit that innovations in delivery systems, precision medicine, and AI-assisted drug design will catalyze the clinical translation of CRMP2-based, non-opioid analgesics, offering a paradigm shift in chronic pain management. Full article

Background: Antibody–drug conjugates (ADCs) have evolved from early heterogeneous constructs into a mature therapeutic platform with exponential clinical relevance. This review highlights recent advances in ADC design and development, with emphasis on antigen selection, antibody engineering, linker and payload innovation, site-specific conjugation, clinical translation, toxicity, resistance, and emerging data-driven approaches. Methods: The review draws on the literature published from 2019 to the recent clinical and regulatory developments relevant to approved and late-stage ADCs, emphasizing the advances in target biology, antibody formats, linker chemistry, payload classes, conjugation technologies, developability assessment, and computational or artificial intelligence-assisted design strategies. Results: ADC development has evolved with improved target selection, enhanced internalization and tumor selectivity, and the use of engineered, bispecific, biparatopic, and fragment-based antibody formats. Linker and payload innovation has expanded beyond traditional microtubule inhibitors to include topoisomerase I inhibitors, DNA-damaging agents, and emerging dual-payload or non-cytotoxic strategies. Site-specific conjugation and improved control of drug-to-antibody ratio have increased stability, pharmacokinetic performance, and manufacturability. Clinically, ADCs are being used across a broader range of malignancies and treatment settings, although toxicities and resistance mechanisms remain an important limitations. Computational methods and artificial intelligence are increasingly being explored for target discovery, molecular optimization, toxicity prediction, and model-informed clinical development. Conclusions: ADCs are transitioning toward a more integrated, design-driven platform in which antigen biology, antibody format, chemistry, and computational prediction are jointly optimized. Future progress will depend on improved standardization, biomarker-guided development, and interdisciplinary approaches to enhance its therapeutic index and expand its applications beyond oncology. Full article

Introduction: Ado-trastuzumab emtansine (T-DM1) is a targeted agent for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, which combines the anti-tumor activity of trastuzumab with the cytotoxic effect of DM1, a microtubule inhibitor. Although T-DM1 has improved outcomes in patients with HER2-positive breast cancer, portal hypertension may occur during treatment in the absence of overt cirrhosis on liver biopsy. These clinical and pathological features are consistent with porto-sinusoidal vascular disorder (PSVD). This study aimed to summarize the reported clinical, biochemical, imaging, histological, therapeutic, and prognostic features of T-DM1-associated PSVD. Methods: PubMed and Web of Science were searched for published cases of T-DM1-associated PSVD. Given the evolving terminology of PSVD, related terms, including non-cirrhotic portal hypertension and nodular regenerative hyperplasia, were also included in the search strategy. If the patient has a recorded history of T-DM1 exposure and the liver biopsy results meet PSVD criteria, the case is included regardless of whether there is clinical, endoscopic, or imaging evidence of portal hypertension. Cases without liver biopsy or with features suggestive of overt cirrhosis were excluded. Patient-level data were extracted and descriptively summarized, including demographic characteristics, clinical manifestations, biochemical indicators, imaging examination results, liver biopsy results, treatment methods, and prognosis. Unreported data were considered missing values and were not imputed. Results: Seven eligible articles comprising eight patients were identified. All patients were female, with a mean age of 60.38 years and a median age of 62.50 years. The interval from T-DM1 initiation to PSVD diagnosis ranged from 6 to 30 months. When reported, the mean interval from treatment initiation to symptom onset was 18.3 months. Thrombocytopenia and splenomegaly were observed in 7 of 8 patients. Mild elevations in alanine aminotransferase and aspartate aminotransferase were observed in all patients. Liver biopsy showed thinned and disorganized hepatic plates accompanied by nodular regeneration of hepatocytes in six patients. Clinical improvement was observed after discontinuation or modification of T-DM1 in most cases. Conclusions: T-DM1-associated PSVD is a rare but clinically significant complication that may develop months after treatment initiation. It commonly presents with thrombocytopenia, splenomegaly, gastrointestinal bleeding, or mild liver biochemical abnormalities in the absence of overt cirrhosis. Early recognition of unexplained platelet decline, splenic enlargement, or portal hypertension-related findings during T-DM1 therapy may facilitate timely diagnosis and individualized management. Withdrawal or modification of the suspected drug may contribute to clinical improvement, although further studies are needed to clarify the mechanism and optimal management strategy. Full article

Hepatoblastoma (HB), the most common pediatric liver cancer, exhibits marked variability in therapeutic response despite minimal genetic heterogeneity, implicating epigenetic regulation as a key driver of tumor behavior. Among these, polycomb repressor complexes (PRC) remain poorly explored as therapeutic targets. Integrative analysis of samples from patients with HB and public datasets identified BMI1, a core component of PRC1, as significantly upregulated, with high expression strongly associated with aggressive disease and poor survival. Functional screening of epigenetic inhibitors across 15 HB cell lines revealed BMI1 inhibition as the most effective therapeutic strategy, with strong concordance between in vitro predictions and in vivo responses in patient-derived xenograft (PDX) models. The BMI1 inhibitor PTC596 demonstrated the highest potency, consistently suppressing tumor growth across models. Mechanistically, PTC596 induced BMI1 degradation, reduced histone H2A ubiquitination, impaired microtubule dynamics, and restored intrinsic apoptosis by shifting the BCL2–BAX balance, leading to caspase-3/7 activation. Transcriptomic profiling confirmed apoptosis as the most significantly enriched pathway. In vivo, PTC596 markedly reduced tumor burden and proliferation while inducing pro-apoptotic signaling, without detectable toxicity. Together, these findings establish BMI1 as a critical oncogenic dependency in HB, demonstrate the value of robust preclinical tumor modeling for therapeutic validation, and identify PTC596 as a promising, mechanism-based treatment strategy. Full article

Background/Objectives. Breast cancer is the most frequently diagnosed cancer worldwide, with approximately 15% classified as Triple-Negative Breast Cancer (TNBC). TNBC is characterized by the absence of estrogen receptor (ER) and progesterone receptor (PR), and the lack of HER2 overexpression, limiting use of targeted therapies. Current TNBC treatment relies heavily on chemotherapy, most commonly taxanes including paclitaxel that stabilize microtubules, disrupt chromosome separation and induce apoptosis. TNBCs frequently develop chemoresistance after multiple treatment cycles, highlighting a critical unmet need for novel therapeutic strategies. This study addresses this challenge by targeting salt-inducible kinase 2 (SIK2), which is overexpressed in 85% of TNBCs compared to normal breast tissue. Methodes. In collaboration with Arrien Pharmaceuticals and Greenfire Biologics, we developed ARN-3261/GRN-300, a novel orally bioavailable SIK2 inhibitor and evaluated its ability to sensitize TNBC cells to paclitaxel in vitro and in vivo. Results. GRN-300 demonstrated strong synergy with paclitaxel in all eight TNBC cell lines tested, as indicated by favorable combination indices. In xenograft models, the combination therapy significantly enhanced tumor growth inhibition and prolonged survival compared to either agent alone. Mechanistic studies showed that GRN-300 disrupts the anaphase-promoting complex/cyclosome (APC/C) pathway by downregulating key mitotic regulators, including CDC27, CDK1, and PLK1, thereby potentiating G2/M cell cycle arrest and apoptosis. Conclusions. Together, these findings establish GRN-300 as a promising therapeutic agent that enhances paclitaxel efficacy through complementary disruption of mitotic regulatory pathways, providing strong preclinical rationale for clinical development in TNBC. Full article

The taxane family of compounds, including paclitaxel, docetaxel (Taxotere), and cabazitaxel (Jevtana), are common drugs used in chemotherapy for the frontline treatment of most major types of cancer. Alopecia, the dramatic loss of hair, is a common side effect that became a symbol of the suffering of many cancer patients. Concerted efforts have been made to understand the mechanism of taxane toxicity to hair follicles and, thus, prevention methods. Taxanes act by stabilizing cellular microtubules, which consequently cause mitotic arrest and then failure, as microtubules play critical functions in chromosome segregation. Hair follicle matrix cells are highly proliferative and thus are exceedingly sensitive to taxanes. We review the cellular mechanism-based strategies under investigation to counter taxane-induced hair follicle damage. These include the application of cyclin kinase inhibitors to block mitotic entry, the practical method using scalp cooling to reduce exposure of scalp hair follicles to drugs during infusion, the requirement of p53 action for hair follicle damage, and the recently discovered method of using low-intensity ultrasound to break taxane-stabilized microtubules and thus reverse taxane toxicity in hair follicle matrix cells. The concept of low-intensity ultrasound as an antidote to taxanes may have the potential to provide a practical and compelling strategy to counter alopecia in cancer treatment using taxanes. Tweet: Taxanes (paclitaxel/docetaxel) are powerful microtubule-stabilizing cancer drugs, but they also cause adverse effects, including alopecia. New research discoveries of temporary microtubule disruption by low-intensity ultrasound may counteract taxane toxicity and prevent alopecia during cancer chemotherapy. “Mechanistic-based strategies for the prevention of taxane-induced hair follicle damage in cancer chemotherapy” OUTLINE: 1. Taxane/paclitaxel mechanism of action in cancer therapy. 2. Taxane side effects: Alopecia (hair loss). 3. p53 dependence of taxane-induced hair follicle damage. 4. Research efforts to counter taxane -induced alopecia by CDK4/6i. 5. Prevention of taxane chemotherapy side effects using scalp cooling. 6. Discovery of low-intensity ultrasound as an antidote for taxane cytotoxicity, and potential prevention of alopecia in chemotherapy using taxanes. 7. Summary and prospective. Full article

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) possesses dual enzymatic functions, i.e., kinase and E3 ubiquitin ligase activities, orchestrating proliferation, survival, apoptosis, DNA damage response, and immune modulation. Recent genomic and mechanistic studies have revealed MAP3K1’s paradoxical, context-dependent roles as both an oncogene and a tumor suppressor. We discuss MAP3K1’s multidomain architecture, featuring an N-terminal RING and PHD domain (E3 ligase activity), a TOG domain (microtubule dynamics), and a C-terminal kinase domain, enabling the integration of c-jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and nuclear factor kappa B (NF-κB) signaling pathways. MAP3K1 functions as a molecular switch balancing survival and apoptosis, with caspase-3 cleavage at Asp878 activating pro-apoptotic JNK/p38 signaling. Genomic analyses across >35 cancer types reveal MAP3K1 alterations at frequencies of <1–14%, highest in breast and endometrial cancers. These alterations show tissue specificity: loss-of-function mutations predominate in hormone receptor-positive breast cancer with a favorable prognosis, whereas gain-of-function mutations in melanoma activate oncogenic ERK signaling. MAP3K1 mutations predict response to mitogen-activated protein kinase kinase (MEK) and phosphoinositide 3-kinase (PI3K) inhibitors, with mutant cancers showing higher MEK inhibitor response than wild-type tumors. Despite substantial progress, critical gaps remain regarding MAP3K1’s E3 ligase substrates, context-dependent activity determinants, and therapeutic strategies. Addressing these through inhibitor development, biomarker validation, and mechanistic studies will accelerate potential clinical translation of MAP3K1 biology. Full article

Background/Objectives: SETD2 is a dual-function methyltransferase important for methylation of histone H3 at lysine 36 and α-tubulin in spindle microtubules. Genetic inactivation of SETD2 during oncogenesis drives loss of H3K36me3, genomic instability, and cancer progression. This study asked if disruption of genomic stability was a canonical feature of SETD2 inactivation via different pathways. Methods: We evaluated the impact of EPZ-719, a pharmacologic SETD2 inhibitor, and an H3.3K36M mutant histone (“oncohistone”) that binds and sequesters SETD2, on methylation activity and genomic stability in human cell lines. SETD2 activity was measured using in vitro methylation assays, H3K36me3 loss confirmed by Western analysis, and mitotic defects, specifically micronuclei and chromatin bridges, quantified with cytogenetic analysis. Results: EPZ-719 caused a dose- and time-dependent reduction in SETD2 activity on both histone and tubulin substrates, accompanied by significant increases in chromatin bridges and micronuclei in retinal pigmented epithelial (RPE-1) and 786-O ccRCC cells. Similarly, oncohistone expression markedly decreased SETD2 function, as determined by H3K36me3 levels, and induced comparable mitotic defects in 786-O cells, and aneuploidy in two chondrocyte cell lines expressing the H3.3K36M oncohistone. Combining EPZ-719 with H3.3K36M expression did not exacerbate mitotic defects beyond either oncohistone or pharmacologic inhibition alone, consistent with inhibition of SETD2 as their shared underlying mechanism of action. Conclusions: Pharmacologic inhibition and oncohistone-mediated sequestration of SETD2 converge on the induction of mitotic defects, underscoring SETD2’s essential role in maintaining genomic stability. Identification of loss of genomic stability as a canonical feature of SETD2 inactivation points to a potential therapeutic liability associated with targeting SETD2 in cancers where it is overexpressed and reveals a mechanism that could contribute to the progression of cancers expressing oncohistone mutations. Full article

Tau protein, a microtubule-associated protein widely distributed in the central nervous system, aggregates abnormally and forms neurofibrillary tangles in neurodegenerative diseases. Particularly in Alzheimer’s disease, pathological tau protein aggregates disrupt the structure and function of neurons, triggering other neurodegenerative-related processes such as neuroinflammation and amyloid plaque formation, and finally leading to neuronal death. Several classes of drugs targeting neurofibrillary tangles have recently been studied, with tau protein aggregation inhibitors as a key research direction. In the context of emerging therapeutic perspectives, this review aims to provide an updated, practical overview of currently available tau protein aggregation inhibitors and future research directions. The first part of the manuscript highlights the pathophysiological basics of tau protein aggregation and tau-related changes in neurodegenerative disorders, with a focus on Alzheimer’s disease pathology. Subsequently, the most relevant classes of drugs that inhibit tau protein aggregation, including small-molecule inhibitors and natural compounds, are presented, with examples from recent clinical trials. Finally, beyond summarizing established classes of tau aggregation inhibitors, this review places particular emphasis on emerging and comparatively underexplored compounds with dual activity against both tau and amyloid-β pathology. The originality and novelty of this work arise from the systematical analysis of recent preclinical and clinical evidence with a translational, practice-oriented perspective, highlighting mechanistic convergence, repurposing opportunities, and therapeutic combinations that may better reflect the multifactorial nature of neurodegenerative diseases. Thus, this work provides a forward-looking framework for future drug development and identifies promising candidates that may shape the next generation of disease-modifying therapies. Full article

In this report, we describe the synthesis and full spectroscopic characterization of a previously unreported podophyllotoxin (PTOX) analogue bearing a second 3,4,5-trimethoxyphenyl (TMP) unit at the C-4 position through an ester linkage. This dual-TMP PTOX derivative is obtained from a brominated PTOX intermediate. In this precursor, the bromine atom is located on the TMP aromatic ring at the 2′-position. The new compound was fully characterized by proton (¹H), carbon-13 (¹³C), heteronuclear single-quantum coherence (HSQC), and distortionless enhancement by polarization transfer (DEPT) NMR spectroscopy. Ultraviolet–visible (UV-Vis) spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, mass spectrometry and elemental analysis were also performed to confirm the structure and purity of the synthesized ester derivative. Full article

Chalcones have garnered significant research interest due to their various medical bioactivities. Several chalcone compounds have been approved for marketing and clinical use in the treatment of various diseases. A critical aspect of the action of chalcones is their effect on microtubules. They are considered an excellent target for chemotherapeutic agents for the treatment of cancer. Consequently, scientists are constantly developing novel chalcone drug agents and also innovative drug delivery strategies. In this manuscript, we report the first synthesis of 12 new visible-light-activated, photoswitchable chalcone-based microtubule inhibitors (17a–17l). Among the obtained compounds, one photoswitch demonstrated light-dependent cytotoxicity in the PC-3 cancer cell line. The IC₅₀ value of the Z conformer was determined to be 4.75 ± 1.00 μM after 48 h of treatment. The E conformer exhibited slightly lower activity compared to the Z conformer, with an IC₅₀ value of 5.80 ± 0.80 µM following 48 h of incubation. In this study, NMR and UV spectroscopy, along with computational methods, were employed. Full article

Background/Objectives: Cancer persists as a leading concern in the current medical field, and current therapies are limited by toxicity, cost, and resistance. Targeted inhibition of tubulin polymerization is considered as a promising therapeutic strategy for cancer treatment. Methods: Thirty-one new tubulin polymerization inhibitors were designed via molecular hybridization techniques, and BLI technology was employed to quantitatively investigate their interactions with tubulin. Antiproliferative activities against MCF-7, MDA-MB-231, A549, and HeLa cell lines was evaluated using the CCK8 assay. Apoptosis induction and cell cycle arrest were analyzed by flow cytometry. The anti-tumor activity of compound B6 was validated in a mouse melanoma tumor model. Results: Compounds exhibited varying degrees of antiproliferative activity against four tumor cell lines. Among them, compound B6 was the most promising candidate and displayed strong broad-spectrum anticancer activity with an average IC₅₀ value of 2 μM. The mechanism studies revealed that compound B6 inhibited tubulin polymerization in vitro, disrupted cell microtubule networks, and arrested the cell cycle at G2/M phase. Furthermore, B6 displayed significant in vivo antitumor efficacy in a melanoma tumor model with tumor growth inhibition rates of 70.21% (50 mg/kg). Conclusions: This work shows that B6 is a promising lead compound deserving further investigation as a potential anticancer agent. Full article

Background: Hypoxia-inducible factor-1α (HIF-1α) is a well-known transcriptional regulator that mediates a broad spectrum of cellular responses to hypoxia, including angiogenesis, extracellular matrix remodeling, and metabolic reprogramming. These activities can be achieved by upregulation of numerous genes, such as vascular endothelial growth factors, fibroblast growth factors, and platelet-derived growth factors, which are involved in the growth regulation of normal tissues and solid tumors. Notably, HIF-1α-mediated regulation of the solid tumor’s microenvironment effectively modulates tumor sensitivity to anticancer therapies and thereby can contribute to disease progression. Methods: The study was performed on breast, lung and prostate cancer cell lines. Protein expression was examined by western blotting. Antitumor activity of 2-ANPC was measured by syngeneic 4T1 breast cancer mouse model. Results: We show here that a 2-aminopyrrole derivative (2-amino-1-benzamido-5-(2-(naphthalene-2-yl)-2-oxoethylidene)-4-oxo-4,5-dihydro-1-H-pyrrole-3-carboxamide—2-ANPC), previously shown as a potent microtubule-targeting agent, effectively downregulates HIF-1α expression in a broad spectrum of cancer cell lines, including breast, lung, and prostate cancer. The downregulation of HIF-1α expression in 2-ANPC-treated cancer cells was due to enhanced proteasome-mediated degradation, whereas the proteasome inhibitor MG-132 effectively reversed this downregulation. 2-ANPC’s potency in downregulating HIF-1α was also shown in vivo by using the 4T1 breast cancer syngraft model. Importantly, this 2-aminopyrrole derivative also downregulated the expression of vascular endothelial growth factor receptors 1 and 3 (VEGFR1 and 3) in 4T1 tumors, which correlated with decreased tumor weight and size. As expected, an increase in apoptotic (i.e., cleaved caspase-3-positive) cells was detected in 4T1 tumors treated with 2-aminopyrrole derivative. Lastly, using various computational tools, we identified four potential binding sites for 2-ANPC to interact with HIF-1α, HIF-1β, and the p300 complex. Conclusions: Collectively, we show here, for the first time, that HIF-1α is a novel molecular target for the 2-aminopyrrole derivative (2-ANPC), thereby illustrating it as a potential scaffold for the development of potent chemotherapeutic agents with anti-angiogenic activity. Full article

Gliomas are the most common malignant primary brain tumors in adults. The treatment of high-grade gliomas is very limited due to their diffuse infiltration, high plasticity, and resistance to conventional therapies. Although they were long considered passive massive lesions, they are now regarded as functionally integrated components of neural circuits, as they form authentic electrochemical synapses with neurons. This allows them to mimic neuronal activity to drive tumor growth and invasion. Ultrastructural studies show presynaptic vesicles in neurons and postsynaptic densities in glioma cell membranes, while electrophysiological recordings detect postsynaptic currents in tumor cells. Tumor microtubules (TMs), dynamic cytoplasmic protrusions enriched in AMPA receptors, are the structures responsible for glioma–glioma and glioma–neuron connectivity, also contributing to treatment resistance and tumor network integration. In these connections, neurons release glutamate that mainly activates their AMPA receptors in glioma cells, while gliomas release excess glutamate, causing excitotoxicity, altering the local excitatory-inhibitory balance, and promoting a hyperexcitable and pro-tumorigenic microenvironment. In addition, certain gliomas, such as diffuse midline gliomas, have altered chloride homeostasis, which makes GABAergic signaling depolarizing and growth promoting. Synaptogenic factors, such as neuroligin-3 and BDNF, further enhance glioma proliferation and synapse formation. These synaptic and paracrine interactions contribute to cognitive impairment, epileptogenesis, and resistance to surgical and pharmacological interventions. High functional connectivity within gliomas correlates with shorter patient survival. Therapies such as AMPA receptor antagonists (perampanel), glutamate release modulators (riluzole or sulfasalazine), and chloride cotransporter inhibitors (NKCC1 blockers) aim to improve outcomes for patients. Full article