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The Journal of Pharmacology and... Jun 2024Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease...
Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease and acquired drug resistance to conventional chemotherapies such as taxanes. Colchicine binding site inhibitors (CBSIs) are attractive alternatives to taxanes because they could potentially achieve oral bioavailability and overcome drug resistance associated with the prolonged use of taxanes. VERU-111 is one of the most advanced CBSIs that is orally available, potent, well-tolerated, and has shown good efficacy in several preclinical solid tumor models. Here, we demonstrate for the first time the potency of VERU-111 as well as its efficacy at inhibiting tumor growth and metastasis in an orthotopic ovarian cancer mouse model. VERU-111 has nanomolar potency against ovarian cancer cell lines and strongly inhibits colony formation, proliferation, invasion, and migration. VERU-111 disrupts microtubule formation to induce mitotic catastrophe and, ultimately, apoptosis in a concentration-dependent manner. The efficacy of VERU-111 was comparable with standard chemotherapy paclitaxel, the current first-line treatment for ovarian cancer, with no observed synergy with combination paclitaxel + VERU-111 treatment. , VERU-111 markedly suppressed ovarian tumor growth and completely suppressed distant organ metastasis. Together, these results support VERU-111 for its potential as a novel therapy for ovarian cancer, particularly for late-stage metastatic disease. VERU-111 is an investigational new drug and has comparable efficacy as paclitaxel in suppressing tumor cell proliferation, colony formation, and migration in ovarian cancer models and has potent anti-tumor and anti-metastatic activity in an orthotopic ovarian cancer mouse model. VERU-111 has low systemic toxicity and, unlike paclitaxel, is orally bioavailable and is not a substrate for the major drug efflux transporters, making it a promising and attractive alternative to taxane-based therapy.
PubMed: 38936977
DOI: 10.1124/jpet.124.002298 -
The Journal of Pharmacology and... Jun 2024Estrogen receptor (ER)-negative breast cancers are known to be aggressive and unresponsive to anti-estrogen therapy, and triple negative breast cancers are associated...
Estrogen receptor (ER)-negative breast cancers are known to be aggressive and unresponsive to anti-estrogen therapy, and triple negative breast cancers are associated with poor prognosis and metastasis. Thus, new targeted therapies are needed. FOXM1 is abundantly expressed in human cancers and implicated in protecting tumor cells from oxidative stress by reducing the levels of intracellular reactive oxygen species (ROS). Aspirin, a prototypical anti-cancer agent with deleterious side effects, has been modified to release nitric oxide and hydrogen sulfide, called NOSH-aspirin (NOSH-ASA), generating a 'safer' class of new anti-inflammatory agents. We evaluated NOSH-ASA against (ER)-negative breast cancer using cell lines and a xenograft mouse model. NOSH-ASA strongly inhibited growth of MDA-MB-231 and SKBR3 breast cancer cells with low ICs of 90{plus minus}5 and 82{plus minus}5 nM, respectively, with marginal effects on a normal breast epithelial cell line. NOSH-ASA inhibited cell proliferation, caused G/G phase arrest, increased apoptosis, and was associated with increases in ROS. In MDA-MB-231 cell xenografts, NOSH-ASA reduced tumor size markedly, which was associated with reduced proliferation (decreased PCNA expression), induction of apoptosis (increased TUNEL positive cells), and increased ROS, while NF-kB and FoxM1 that were high in untreated xenografts were significantly reduced. mRNA data for FoxM1, p21 and CyclinD1 corroborated with the respective protein expressions and arrest of cells. Taken together, these molecular events contribute to NOSH-ASA mediated growth inhibition and apoptotic death of (ER)-negative breast cells in vitro and in vivo. Additionally, as a ROS-inducer and FOXM1-inhibitor, NOSH-ASA has potential as a targeted therapy. In this investigation, we examined the cellular effects and xenograft tumor inhibitory potential of NOSH-aspirin, an NO and HS-donating hybrid, against ER-negative breast cancer, which currently lacks effective therapeutic options. The induction of reactive oxygen species and subsequent downregulation of FOXM1 represents a plausible mechanism contributing to the observed decrease in cell proliferation and concurrent increase in apoptosis. NOSH-ASA demonstrated a remarkable reduction in tumor size by 90% without inducing any observable gross toxicity, underscoring its promising translational potential.
PubMed: 38936976
DOI: 10.1124/jpet.124.002240 -
The Kobe Journal of Medical Sciences Jun 2024Olfactory neuroblastoma (ONB) is an uncommon malignant tumor and is usually treated by a multidisciplinary approach includes surgery, radiotherapy, and chemotherapy. A...
Olfactory neuroblastoma (ONB) is an uncommon malignant tumor and is usually treated by a multidisciplinary approach includes surgery, radiotherapy, and chemotherapy. A 62 years-old male had a tumor in the nasal cavity and diagnosed as ONB with Kadish A stage. Anterior skull base surgery was performed as radical treatment. Since the surgical margin was negative, no postoperative radiotherapy was administered. 14 years after the surgery, bilateral otitis media with effusion (OME) was occurred, we found the recurrence tumor at bilateral retropharyngeal lymph node (RPLN) which surrounded the internal carotid arteries. Since these were unresectable, we planned chemoradiotherapy which was 70Gy of intensity modulated radiotherapy combined with two courses of carboplatin and etoposide. The tumor volume was reduced and bilateral OME were improved. He has been alive for 3 years after salvage treatment. Although ONB has a relatively good prognosis, it is known to often cause cervical lymph node metastasis. Grades III and IV of Hyams classification are considered high risk. This case, initial tumor was limited in the nasal cavity and its clinical classification was early stage, but Hyams classification was grade III. In reference to this case, considering that RPLN metastasis are difficult to radically resect at the salvage surgery, including this area in postoperative radiotherapy was considered an option.
Topics: Humans; Male; Esthesioneuroblastoma, Olfactory; Middle Aged; Lymphatic Metastasis; Nose Neoplasms; Nasal Cavity; Skull Base; Neoplasm Recurrence, Local; Chemoradiotherapy
PubMed: 38936878
DOI: 10.24546/0100489917 -
PloS One 2024Colorectal cancer (CRC) is the third most common malignancy cause of cancer-related mortality worldwide. Epithelial-mesenchymal transition (EMT) promotes cancer...
Colorectal cancer (CRC) is the third most common malignancy cause of cancer-related mortality worldwide. Epithelial-mesenchymal transition (EMT) promotes cancer metastasis and a tumour-based Glasgow EMT score was associated with adverse clinical features and poor prognosis. In this study, the impact of using the established five tumour-based EMT markers consisting of E-cadherin (E-cad), β-catenin (β-cat), Snail, Zeb-1, and Fascin in combination with the stromal periostin (PN) on the prediction of CRC patients' prognosis were invesigated. Formalin-fixed paraffin-embedded tissues of 202 CRC patients were studies the expressions of E-cad, β-cat, Snail, Zeb-1, Fascin, and PN by immunohistochemistry. Individually, cytoplasmic Fascin (Fc), cytoplasmic Snail (Sc), nuclear Snail (Sn), stromal Snail (Ss), and stromal PN (Ps) were significantly associated with reduced survival. A combination of Ps with Fc, Fs, and Sn was observed in 2 patterns including combined Fc, Fs, and Ps (FcFsPs) and Fc, Sn, and Ps (FcSnPs). These combinations enhanced the prognostic power compared to individual EMT markers and were independent prognostic markers. As the previously established scoring method required five markers and stringent criteria, its clinical use might be limited. Therefore, using these novel combined prognostic markers, either FcFsPs or FcSnPs, may be useful in predicting CRC patient outcomes.
Topics: Humans; Colorectal Neoplasms; Snail Family Transcription Factors; Cell Adhesion Molecules; Prognosis; Female; Male; Middle Aged; Carrier Proteins; Microfilament Proteins; Epithelial-Mesenchymal Transition; Aged; Biomarkers, Tumor; Adult; Cadherins; Transcription Factors; beta Catenin; Aged, 80 and over; Periostin
PubMed: 38935747
DOI: 10.1371/journal.pone.0304666 -
PLoS Biology Jun 2024
PubMed: 38935591
DOI: 10.1371/journal.pbio.3002708 -
Indian Journal of Dental Research :... Jan 2024Melanoma is the ninth most prevalent and the second most lethal tumour. The aetiology and pathogenesis remain uncertain. It occurs in elderly people, over the fifth...
Melanoma is the ninth most prevalent and the second most lethal tumour. The aetiology and pathogenesis remain uncertain. It occurs in elderly people, over the fifth decade, and is predominant in males. Clinically, they present as an asymptomatic macular or nodular growth. The prognosis is impacted by the size of the tumour and distant metastases. Patients with distant metastases have a 5-year survival rate of less than 30%, constituting metastasis as the major cause of melanoma-related fatality. Currently, the mainstay of treatment for metastatic melanoma is immunotherapy due to the inoperable state, radioresistant nature of the tumour and high chances of cytotoxicity in chemotherapy. A senile male patient, who was diagnosed with oral malignant melanoma of the maxillary buccopalatal gingiva with distant metastasis to the liver and the prostate, is reported here. Although metastasis to the liver is common among malignant melanomas, in this case metastasis to the prostate gland highlights the rarity.
Topics: Humans; Male; Melanoma; Prostatic Neoplasms; Mouth Neoplasms; Liver Neoplasms; Gingival Neoplasms; Aged
PubMed: 38934760
DOI: 10.4103/ijdr.ijdr_376_23 -
Archivio Italiano Di Urologia,... Jun 2024Breast cancer (BrC) is the most frequently diagnosed malignancy in woman and most BrC related deaths are due to metastasis. BrC frequently metastasizes to the lymph...
Breast cancer (BrC) is the most frequently diagnosed malignancy in woman and most BrC related deaths are due to metastasis. BrC frequently metastasizes to the lymph nodes, liver, lung, bone and brain while the urinary bladder is considered as an unusual site for breast metastasis. We report a case of bladder metastasis identified in a patient with past BrC history, presenting with hematuria, low urinary tract symptoms, and hydronephrosis.
Topics: Humans; Female; Urinary Bladder Neoplasms; Breast Neoplasms; Linitis Plastica; Middle Aged; Hematuria
PubMed: 38934524
DOI: 10.4081/aiua.2024.12483 -
Nanoscale Advances Jun 2024Tumors pose a significant threat to human health, and their occurrence and fatality rates are on the rise each year. Accurate tumor diagnosis is crucial in preventing...
Tumors pose a significant threat to human health, and their occurrence and fatality rates are on the rise each year. Accurate tumor diagnosis is crucial in preventing untimely treatment and late-stage metastasis, thereby reducing mortality. To address this, we have developed a novel type of hybrid nanogel called γ-FeO@PNIPAM/PAm/CTS, which contains iron oxide nanoparticles and poly(-isopropyl acrylamide)/polyacrylamide/chitosan. The rationale for this study relies on the concept that thermosensitive PNIPAM has the ability to contract when exposed to elevated temperature conditions found within tumors. This contraction leads to a dense clustering of the high-loading γ-FeO nanoparticles within the nanogel, thus greatly enhancing the capabilities of MRI. Additionally, the amino groups in chitosan on the particle surface can be converted into ammonium salts under mildly acidic conditions, allowing for an increase in the charge of the nanogel specifically at the slightly acidic tumor site. Consequently, it promotes the phagocytosis of tumor cells and effectively enhances the accumulation and retention of nanogels at the tumor site. The synthesis of the hybrid nanogels involves a surfactant-free emulsion copolymerization process, where vinyl-modified γ-FeO superparamagnetic nanoparticles are copolymerized with the monomers in the presence of chitosan. We have optimized various reaction parameters to achieve a high loading content of the superparamagnetic nanoparticles, reaching up to 60%. The achieved value of 517.74 mM S significantly surpasses that of the clinical imaging contrast agent Resovist (approximately 151 mM S). To assess the performance of these magnetic nanogels, we conducted experiments using Cal27 oral tumors and 4T1 breast tumors in animal models. The nanogels exhibited temperature- and pH-sensitivity, enabling magnetic targeting and enhancing diagnosis through MRI. The results demonstrated the potential of these hybrid nanogels as contrast agents for magnetic targeting in biomedical applications.
PubMed: 38933853
DOI: 10.1039/d4na00014e -
Frontiers in Endocrinology 2024The growing incidence of differentiated thyroid cancer (DTC) have been linked to insulin resistance and metabolic syndrome. The imperative need for developing effective...
OBJECTIVES
The growing incidence of differentiated thyroid cancer (DTC) have been linked to insulin resistance and metabolic syndrome. The imperative need for developing effective diagnostic imaging tools to predict the non-iodine-avid status of lung metastasis (LMs) in differentiated thyroid cancer (DTC) patients is underscored to prevent unnecessary radioactive iodine treatment (RAI).
METHODS
Primary cohort consisted 1962 pretreated LMs of 496 consecutive DTC patients with pretreated initially diagnosed LMs who underwent chest CT and subsequent post-treatment radioiodine SPECT. After automatic lesion segmentation by SE V-Net, SE Net deep learning was trained to predict non-iodine-avid status of LMs. External validation cohort contained 123 pretreated LMs of 24 consecutive patients from other two hospitals. Stepwise validation was further performed according to the nodule's largest diameter.
RESULTS
The SE-Net deep learning network yielded area under the receiver operating characteristic curve (AUC) values of 0.879 (95% confidence interval: 0.852-0.906) and 0.713 (95% confidence interval: 0.613-0.813) for internal and external validation. With the LM diameter decreasing from ≥10mm to ≤4mm, the AUCs remained relatively stable, for smallest nodules (≤4mm), the model yielded an AUC of 0.783. Decision curve analysis showed that most patients benefited using deep learning to decide radioactive I treatment.
CONCLUSION
This study presents a noninvasive, less radioactive and fully automatic approach that can facilitate suitable DTC patient selection for RAI therapy of LMs. Further prospective multicenter studies with larger study cohorts and related metabolic factors should address the possibility of comprehensive clinical transformation.
Topics: Humans; Thyroid Neoplasms; Iodine Radioisotopes; Lung Neoplasms; Female; Male; Middle Aged; Adult; Aged; Deep Learning; Retrospective Studies; Tomography, Emission-Computed, Single-Photon; Cohort Studies
PubMed: 38933823
DOI: 10.3389/fendo.2024.1429115 -
Frontiers in Endocrinology 2024Exosomes, as pivotal entities within the tumor microenvironment, orchestrate intercellular communication through the transfer of diverse molecules, among which... (Review)
Review
Exosomes, as pivotal entities within the tumor microenvironment, orchestrate intercellular communication through the transfer of diverse molecules, among which non-coding RNAs (ncRNAs) such as miRNAs, lncRNAs, and circRNAs play a crucial role. These ncRNAs, endowed with regulatory functions, are selectively incorporated into exosomes. Emerging evidence underscores the significance of exosomal ncRNAs in modulating key oncogenic processes in thyroid cancer (TC), including proliferation, metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, and immunoediting. The unique composition of exosomes shields their cargo from enzymatic and chemical degradation, ensuring their integrity and facilitating their specific expression in plasma. This positions exosomal ncRNAs as promising candidates for novel diagnostic and prognostic biomarkers in TC. Moreover, the potential of exosomes in the therapeutic landscape of TC is increasingly recognized. This review aims to elucidate the intricate relationship between exosomal ncRNAs and TC, fostering a deeper comprehension of their mechanistic involvement. By doing so, it endeavors to propel forward the exploration of exosomal ncRNAs in TC, ultimately paving the way for innovative diagnostic and therapeutic strategies predicated on exosomes and their ncRNA content.
Topics: Humans; Exosomes; Thyroid Neoplasms; RNA, Untranslated; Disease Progression; Tumor Microenvironment; Biomarkers, Tumor; Animals; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic
PubMed: 38933820
DOI: 10.3389/fendo.2024.1337226