Potent Antiproliferative Effects Research Articles

Activity Evaluation and Mode of Action of ICA Against Toxoplasma gondii In Vitro

Toxoplasmosis is a significant zoonotic parasitic disease. Currently, there is no effective vaccine available to prevent human infection, and treatment primarily relies on chemotherapy. However, the lack of specific therapeutic agents and the limitations of existing drugs highlight the urgent need for novel, safe, and effective anti-Toxoplasma gondii (T. gondii) medications. In this study, we evaluated the toxicity of ICA (N-(pyridin-2-yl)-4-(pyridine-2-yl)thiazol-2-amine) to host cells and assessed its inhibitory and anti-proliferative effects on T. gondii tachyzoites. We further investigated the impact of ICA on the ultrastructure of T. gondii using transmission electron microscopy (TEM). Additionally, we measured alterations in mitochondrial membrane potential, superoxide levels, and ATP levels in T. gondii to assess the effect of ICA on mitochondrial function. Our findings demonstrated that ICA exhibits a safe and effective inhibitory effect on T. gondii, with a selectivity index (SI) of 258.25. Notably, ICA demonstrated a more potent anti-proliferative effect than pyrimethamine (PYR). Ultrastructural observations revealed that ICA induces mitochondrial swelling and membrane rupture in T. gondii. Further investigations confirmed that ICA leads to mitochondrial dysfunction in T. gondii. In conclusion, our results suggest that ICA possesses the potential to serve as a lead compound for the development of novel anti-T. gondii therapies.

Gamma-Tocotrienol Inhibits Proliferation and Growth of HSD17B4-Overexpressing HepG2 Liver Cancer Cells.

Hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4) is involved in the progression of hepatocellular carcinoma (HCC). This study aimed to investigate the inhibitory effect of gamma-tocotrienol (γ-T3) on the proliferation and growth of HSD17B4-overexpressing HepG2 cells. HepG2 cells were transfected with empty or HSD17B4-overexpressing plasmids, followed by vitamin E (VE) or γ-T3 treatment. MTS assay, Western blotting, qRT-PCR, and flow cytometry were employed to assess cell proliferation, protein expression, mRNA levels, and apoptosis. HSD17B4 interaction with γ-T3 was assessed by quantifying γ-T3 in the collected precipitate of HSD17B4 using anti-flag magnetic beads. Tumor xenografts were established in NSG mice, and tumor growth was monitored. HSD17B4 overexpression significantly promoted HepG2 cell proliferation, which was effectively counteracted by VE or γ-T3 treatment in a dose-dependent manner. VE and γ-T3 did not exert their effects through direct regulation of HSD17B4 expression. Instead, γ-T3 was found to interact with HSD17B4, inhibiting its activity in catalyzing the conversion of estradiol (E2) into estrone. Moreover, γ-T3 treatment led to a reduction in cyclin D1 expression and suppressed key proliferation signaling pathways, such as ERK, MEK, AKT, and STAT3. Additionally, γ-T3 promoted apoptosis in HSD17B4-overexpressing HepG2 cells. In an in vivo model, γ-T3 effectively reduced the growth of HepG2 xenograft tumors. In conclusion, our study demonstrates that γ-T3 exhibits potent anti-proliferative and anti-tumor effects against HepG2 cells overexpressing HSD17B4. These findings highlight the therapeutic potential of γ-T3 in HCC treatment and suggest its role in targeting HSD17B4-associated pathways to inhibit tumor growth and enhance apoptosis.

Synthesis and Biological Evaluation of Cyclohexane-1,2,3,5-Tetrol Analogs as Potential Lead Candidates for Cancer Therapy

Introduction: A preliminary biological evaluation of ten synthesized analogs, 5a-5j {[5-(E)-benzylidene amino]-1,3,4-thiadiazol-2-yl} cyclohexane-1,2,3,5-tetrol, revealed promising results, positioning these compounds as potential lead candidates for further optimization and preclinical exploration in cancer therapy. Incorporating the 1,3,4-thiadiazol moiety into the structure of the produced analogs considerably improved their anticancer activities, revealing the compound's high potential for cancer treatment. Spectroscopic approaches and structural analysis, such as elemental analysis, IR, ¹H NMR, ¹³C NMR, and MS, were crucial for properly establishing the molecular structures of these analogs and evaluating their anticancer activity. These methodologies laid a solid platform for rationally developing new anticancer medications with increased efficacy and fewer adverse effects. Furthermore, computational tools like molecular docking, ADMET prediction, and drug-likeness evaluation have accelerated the drug development by finding the most promising lead candidates for preclinical and clinical trials. This technique not only saves time and costs, but also raises the chances of producing successful anticancer drugs. Method: The main aim of the current study is to develop, synthesize, in-silico, in-vitro potentials of {5-[(E)-benzylidene amino]-1,3,4-thiadiazol-2-yl} cyclohexane-1,2,3,5-tetrol for a possible anticancer drug to improve their efficiency and selectivity against cancer cells, computational approaches aided in the rational design of these chemicals. Spectroscopic methods verified the chemical structures of the target compounds. The structures show the presence of 1,3,4, thiadiazol also responsible for anticancer activity. The 10 analogs were synthesized and showed encouraging anticancer efficacy in preliminary biological evaluation, suggesting they might be suitable lead candidates for more optimization and preclinical exploration Results: {5-[(E)-benzylidene amino]-1,3,4-thiadiazol-2-yl} cyclohexane-1,2,3,5-tetrol derivatives 5a-5j showed optimum IC50 values in invitro activity by SRB assay using MCF-7 as a strain, the few selected analogs. Conclusion: The study synthesized cyclohexane-1,2,3,5-tetrol analogs and evaluated their potential for cancer therapy. The compounds showed promising cytotoxic activity against various cancer cell lines, with 5c, 5f, 5g, and 5j showing the most potent anti-proliferative effects. These compounds induce apoptosis via mitochondrial dysfunction and cell cycle arrest. Further preclinical investigations are needed to establish their therapeutic potential.

Longikaurin A, a natural ent-kaurane, suppresses proliferation, invasion and tumorigenicity in oral squamous cell carcinoma cell by via inhibiting PI3K/Akt pathway in vitro and in vivo.

Background: Longikaurin A (LK-A), a naturally occurring ent-kaurane diterpenoid, has been identified as a promising anti-cancer agent. This study aims to elucidate the anti-tumorigenic effects of LK-A on oral squamous cell carcinoma (OSCC) cells and to unravel its underlying mechanisms. Methods: In vitro assays, including CCK-8 and EdU, were performed to assess cell viability and proliferation. Transwell migration and invasion assays evaluated cell mobility and invasive potential. Apoptotic effects were analyzed using Annexin V-FITC/PI staining and TUNEL assays. Western blot analysis was conducted to examine protein expression related to cell cycle, apoptosis, and the PI3K/Akt signaling pathway. In vivo experiments involved treating mouse xenograft models with LK-A and evaluating tumor growth and signaling pathway inhibition through immunohistochemistry and Western blot assays. Results: LK-A significantly suppressed cell viability and proliferation in a dose-dependent manner, with IC50 values of 4.36 μM and 4.93 μM at 24 h, and 1.98 μM and 2.89 μM at 48 h for CAL27 and TCA-8113 cells, respectively. EdU assays revealed a reduction in the EdU positive rate, and cell cycle analysis showed G2/M phase arrest. Western blot analysis confirmed decreased expression of CyclinB1 and Cdc2. LK-A significantly inhibited OSCC cell mobility and invasive potential, with downregulation of MMP-2 and MMP-9 expression. Apoptotic effects were confirmed by increased apoptosis, upregulation of Bax and cleaved caspase-3, and downregulation of Bcl-2. LK-A suppressed the PI3K/AKT signaling pathway, as evidenced by reduced phosphorylation of PI3K, AKT, and mTOR. The AKT activator SC79 reversed the antiproliferative and pro-apoptotic effects of LK-A. In vivo, LK-A significantly inhibited tumor growth in mouse xenograft models, with reduced tumor weights and volumes, and no significant loss in body weight. Immunohistochemistry and Western blot assays confirmed the inhibition of p-Akt and Ki-67 expression. Conclusion: These findings suggest that LK-A exerts potent antiproliferative, anti-migratory, and pro-apoptotic effects on OSCC cells through the suppression of the PI3K/AKT signaling pathway, demonstrating its potential as a therapeutic agent for OSCC.

Impact of dyslipidemia and lipid-lowering therapy with statins in patients with neuroendocrine tumors.

Dyslipidemia is a potential unfavorable prognostic factor in neuroendocrine tumors (NETs); conversely, statins proved to have antiproliferative effects in NET cell lines and could be a helpful therapeutic strategy for these patients. The main objective of this observational cohort retrospective study is to explore the associations between dyslipidemia and NET progression and evaluate the potential influence of statins in this context. 393 patients with histologically confirmed gastroenteropancreatic or bronchopulmonary NETs from six Italian centres didicated to NET diagnosis and therapy were included. The cohort included 123 patients with dyslipidemia, 81 of which were taking statins. Clinicopathological data, including patient demographics, tumor characteristics, and treatment details as well as the prevalence, timing of dyslipidemia and hypolipemic therapy were collected. The main outcome measure used is progression-free survival (PFS). Among the 393 patients, 123 (31.3%) had dyslipidemia. Statins were used by 81 (65.8%) dyslipidemic patients, mostly atorvastatin. Median PFS was 87 months overall, 124 months in non-dyslipidemic patients, and 72 months in dyslipidemic patients (p = .268). Dyslipidemic patients on statins had a significantly better median PFS (108 months) than those not on statins (26 months; p = .024). Recurrence-free survival(RFS) was also evaluated, but no significant differences were found. In conclusion, while PFS was lower in dyslipidemic patients compared to non-dyslipidemic patients, the difference was not statistically significant. Statin therapy was associated with improved PFS among dyslipidemic patients, suggesting a potential antiproliferative effect of statins in NETs. These findings warrant further investigation to substantiate the role of statins in the management of NETs.

The Anticancer Activity of Cannabinol (CBN) and Cannabigerol (CBG) on Acute Myeloid Leukemia Cells.

Several cannabis plant-derived compounds, especially cannabinoids, exhibit therapeutic potential in numerous diseases and conditions. In particular, THC and CBD impart palliative, antiemetic, as well as anticancer effects. The antitumor effects include inhibition of cancerous cell growth and metastasis and induction of cell death, all mediated by cannabinoid interaction with the endocannabinoid system (ECS). However, the exact molecular mechanisms are still poorly understood. In addition, their effects on leukemia have scarcely been investigated. The current work aimed to assess the antileukemic effects of CBN and CBG on an acute monocytic leukemia cell line, the THP-1. THP-1 cell viability, morphology and cell cycle analyses were performed to determine potential cytotoxic, antiproliferative, and apoptotic effects of CBN and CBG. Western blotting was carried out to measure the expression of the proapoptotic p53. Both CBN and CBG inhibited cell growth and induced THP-1 cell apoptosis and cell cycle arrest in a dose- and time-dependent manner. CBN and CBG illustrated different dosage effects on THP-1 cells in the MTT assay (CBN > 40 μΜ, CBG > 1 μM) and flow cytometry (CBN > 5 μM, CBG > 40 μM), highlighting the cannabinoids' antileukemic activity. Our study hints at a direct correlation between p53 expression and CBG or CBN doses exceeding 50 μM, suggesting potential activation of p53-associated signaling pathways underlying these effects. Taken together, CBG and CBN exhibited suppressive, cell death-inducing effects on leukemia cells. However, further in-depth research will be needed to explore the molecular mechanisms driving the anticancer effects of CBN and CBG in the leukemia setting.

A Catch-Release Strategy for the Genomics-Driven Discovery of Antiproliferative Furan-Functionalized Peptides.

Furan-functionalized peptides are of significant pharmacological interest due to their pronounced bioactivities and unique potential for orthogonal bioconjugation and derivatization. However, naturally occurring peptides with furyl side chains are exceedingly rare. This study presents a streamlined method to predict and assess the microbial production of peptides incorporating 3-furylalanine (Fua) moieties. The approach integrates genome mining and the reversible, chemoselective tagging of furyl residues, utilizing their unique Diels-Alder reactivity, for mass spectrometry-guided identification of candidate compounds. By employing the rhizonin Fua synthase as a bioinformatic handle and through heterologous reconstitution of Fua biosynthesis, we identified previously unknown Fua biosynthetic pathways in diverse bacterial phyla, including actinomycetes, cyanobacteria, actinobacteria, and g-proteobacteria, suggesting that Fua-containing peptides are remarkably widely distributed. Metabolic profiling by reversible tagging facilitated the detection of native Fua-containing metabolites. The successful adaptation of this method for solid support enabled the direct enrichment of furyl-substituted peptides from complex mixtures. This multi-pronged approach enabled the discovery and characterization of two novel families of Fua cyclopeptides (rubriamides and typhamides) with potent antiproliferative effects against human tumor cells and nematodes. The innovative catch-and-release strategy, in conjunction with genome mining, represents a valuable tool for the discovery of new furan-substituted natural products.

A Catch‐Release Strategy for the Genomics‐Driven Discovery of Antiproliferative Furan‐Functionalized Peptides

Abstract: Furan‐functionalized peptides are of significant pharmacological interest due to their pronounced bioactivities and unique potential for orthogonal bioconjugation and derivatization. However, naturally occurring peptides with furyl side chains are exceedingly rare. This study presents a streamlined method to predict and assess the microbial production of peptides incorporating 3‐furylalanine (Fua) moieties. The approach integrates genome mining and the reversible, chemoselective tagging of furyl residues, utilizing their unique Diels‐Alder reactivity, for mass spectrometry‐guided identification of candidate compounds. By employing the rhizonin Fua synthase as a bioinformatic handle and through heterologous reconstitution of Fua biosynthesis, we identified previously unknown Fua biosynthetic pathways in diverse bacterial phyla, including actinomycetes, cyanobacteria, actinobacteria, and g‐proteobacteria, suggesting that Fua‐containing peptides are remarkably widely distributed. Metabolic profiling by reversible tagging facilitated the detection of native Fua‐containing metabolites. The successful adaptation of this method for solid support enabled the direct enrichment of furyl‐substituted peptides from complex mixtures. This multi‐pronged approach enabled the discovery and characterization of two novel families of Fua cyclopeptides (rubriamides and typhamides) with potent antiproliferative effects against human tumor cells and nematodes. The innovative catch‐and‐release strategy, in conjunction with genome mining, represents a valuable tool for the discovery of new furan‐substituted natural products.

Abstract A013: Prioritization of Eleven-Nineteen-Leukemia (ENL) inhibitors as orally available drug candidates for acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) is the second most prevalent and fatal form of leukemia. The growth of AML cells harboring oncogenic MLL rearrangements relies on The YEATS domain-containing protein ENL. Many small molecule inhibitors targeting ENL have been developed. To prioritize these inhibitors for in vivo studies, a NanoBRET system was introduced to evaluate their cellular permeability and potency. This screening identified Inhibitor 13 as a promising candidate. This inhibitor has remarkable metabolic stability and potent anti-proliferative effects on MLL-fusion leukemia cell lines. In AML-xenografted mice, Inhibitor 13 significantly improved survival. Subsequent optimization efforts led to the development of SR-C-107 (R), which exhibited strong activity against AML both at the cellular level (CC50 (MOLM-13): 1.25 ± 0.18 μM; CC50 (MV4-11): 0.81 ± 0.15 μM) and in vivo. These findings establish SR-C-107 (R) as a compelling candidate for AML treatment and lay the groundwork for the development of next-generation AML inhibitors. Citation Format: Wenshe R. Liu, Xuejiao Guo, Sandeep Alta, Shiqing Xu. Prioritization of Eleven-Nineteen-Leukemia (ENL) inhibitors as orally available drug candidates for acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A013

Discovery of Spirosnuolides A-D, Type I/III Hybrid Polyketide Spiro-Macrolides for a Chemotherapeutic Lead against Lung Cancer.

Four new macrolides, spirosnuolides A-D (1-4, respectively), were discovered from the termite nest-derived Kitasatospora sp. INHA29. Spirosnuolides A-D are 18-membered macrolides sharing an embedded [6,6]-spiroketal functionality inside the macrocycle and are conjugated with structurally uncommon side chains featuring cyclopentenone, 1,4-benzoquinone, hydroxyfuroic acid, or butenolide moieties. Structure elucidation was achieved using a combination of spectroscopic analyses, multiple chemical derivatizations (methylation, methanolysis, Luche reduction, and Mosher's reaction), X-ray diffraction analysis, and computational ECD calculations. Interestingly, genome sequencing analysis suggests that spirosnuolides were biosynthesized through a rare type I/III hybrid polyketide synthase. Importantly, spirosnuolide B displayed potent antiproliferative effects against various cancer cell lines at nanomolar concentrations, particularly against HCC827 cells, an EGFR mutant non-small-cell lung cancer (NSCLC) cell line, with a high safety index value. Based on in vitro studies, the antiproliferative mechanism of spirosnuolide B involved the activation of AMPK signaling, leading to cell cycle arrest and apoptosis in HCC827 cells. Its potent efficacy was also proven in vivo by the effective inhibition of tumor growth in mouse xenograft studies. Moreover, cotreatment with spirosnuolide B and gefitinib, synergistically enhanced the antiproliferative activity and apoptosis, suggesting a potential strategy to overcome gefitinib resistance in EGFR mutant NSCLC.

Potential Antiproliferative and Antimetastatic Effects of Artemisia eriantha: An In Vitro Study Focused on Hepatocarcinoma Cells.

Artemisia eriantha is a subendemic species of the Central Apennine, valued locally for its applications in ancient and traditional medicine for its antibacterial, antifungal, anthelmintic, digestive, and antispasmodic effects. Several of these properties are also found in other species within the same genus, including recent findings highlighting their anti-tumor actions. However, the presence of cytotoxic or anti-tumor activity has never been studied in A. eriantha. The aim of this study was thus to assess the potential anti-proliferative, pro-apoptotic, and antimetastatic effects of this plant using in vitro models of hepatocarcinoma cells (HepG2 and Huh7 cells). Treatment with A. eriantha extract (130 μg/mL) resulted in the reduced proliferation of HepG2 and Huh7 cells, driven by the dysregulation of proteins involved in the cell cycle (such as cyclin D1, cyclin E, and p27) and the activation of the p53-p21 pathway, leading to an increase in apoptotic activity. In addition, the treatment also lowered the healing capability after scratch wounds in Huh7 cells, which are characterized by a remarkable migratory capacity, suggesting that the A. eriantha extract may also be effective in controlling the migration and spread of metastatic cells. In conclusion, A. eriantha extract 130 μg/mL appears to interfere with key factors of HepG2 and Huh7 cell proliferation and invasion and emerges as a potential new adjuvant for the prevention and/or treatment of hepatocellular carcinoma. Additional research is necessary to establish if the effects observed are cell-specific and to elucidate the mechanisms of action and signaling pathways underlying its effectiveness.

Mechanism of melanoma suppression by Prosopis juliflora derived alkaloids: Apoptosis induction and signaling pathway inhibition

BackgroundTraditional medicines remain integral to healthcare worldwide especially in developing countries. Our prior studies highlighted the anti-melanoma potential of Prosopis juliflora leave methanolic extract (PJLME), leading us to further isolate and characterize bioactive compounds from PJLME and evaluate their efficacy against melanoma. In this context, we identified alkaloid fractions derived from PJLME (PJLME-AF) as key agents in PJLME's cytotoxic effect against melanoma cells. PurposeThe purpose of this research was to evaluate the anti-cancer effects and mechanisms of PJLME-AF on melanoma cell lines. MethodsChemical Profiling of PJLME-AF was conducted by using LC-ESI-MS/MS. Cell viability and anti-migratory effects of PJLME-AF were assessed through MTT, wound healing and transwell assays. Mechanistic study of PJLME-AF was explored using ROS generation assay, apoptosis assays (Annexin V) assay, western blot (apoptotic protein, EMT markers, stem cell markers and signalling pathways), qPCR. In-vitro spheroid assay was performed to explored the PJLME-AF cytotoxic effects on tumour spheroid forming ability of melanoma cells. Additionally, the anti-tumor efficacy of PJLME-AF was tested in an in-vivo C57BL/6 mouse model. ResultsPJLME-AF demonstrated potent anti-proliferative, anti-migratory and anti-invasive effects on melanoma cells. Mechanistic study indicates that PJLME-AF strongly induce ROS generation and subsequent apoptotic cell death in melanoma cells. Furthermore, PJLME-AF downregulated epithelial-to-mesenchymal transition (EMT) proteins, stem cell markers and Akt/Erk cell survival proteins providing insights into its molecular mechanisms. Notably, PJLME-AF inhibited spheroid formation and reduced PD-L1 expression. Finally, anti-tumor activity of PJLME-AF was further confirmed in a in-vivo mice model. Additionally, PJLME-AF combined with dacarbazine, exhibited enhanced cytotoxicity on melanoma compared to the drug alone. ConclusionPJLME-AF exhibit promising natural anti-cancer agents for metastatic melanoma treatment. This research contributes to the development of novel, safe, and cost-effective agents for metastatic melanoma treatment and as a potential candidate for further cancer research.

Cytotoxicity of natural and synthetic cannabinoids and their synergistic antiproliferative effects with cisplatin in human ovarian cancer cells.

Cannabinoids are reported to suppress the growth of ovarian cancer cells, but it is unclear whether structural modifications can improve their cytotoxic effects. Herein, an investigation into the antiproliferative effects of natural cannabinoids on human ovarian cancer Caov-3 cells identified cannabidiol (CBD) as the most promising cannabinoid. Furthermore, chemical modifications of CBD yielded a group of derivatives with enhanced cytotoxicity in Caov-3 cells. Two CBD piperazinyl derivatives (19 and 21) showed augmented antiproliferative effects with an IC50 of 5.5 and 4.1µM, respectively, compared to CBD's IC50 of 22.9µM. Further studies suggest that modulation of apoptosis and ferroptosis may contribute to the cytotoxic effects of CBD and its derivatives. In addition, CBD and its derivatives (19 and 21) were explored for their potential synergistic antiproliferative effects in combination with chemotherapeutic agent cisplatin. Compounds 19 or 21 (5µM) combined with cisplatin (1µM) showed a synergistic effect with a combination index of 0.23 and 0.72, respectively. This effect was supported by elevated levels of reactive oxygen species in Caov-3 cells treated with cisplatin combined with 19 or 21. Findings from this study suggest that CBD derivatives with enhanced antiproliferative effects may exert synergistic effects with chemotherapeutic drugs, providing insight into the development of cannabinoid-based adjuvant agents for the management of ovarian cancer.

Prioritization of Eleven-Nineteen-Leukemia Inhibitors as Orally Available Drug Candidates for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is the second most prevalent and fatal form of leukemia. The growth of AML cells harboring oncogenic MLL rearrangements relies on the YEATS domain-containing protein ENL. Many small molecule inhibitors targeting ENL have been developed. To prioritize these inhibitors for in vivo studies, a NanoBRET system was introduced to evaluate their cellular permeability and potency. This screening identified inhibitor 13 as a promising candidate. This inhibitor has remarkable metabolic stability and potent antiproliferative effects on MLL-fusion leukemia cell lines. In AML-xenografted mice, inhibitor 13 significantly improved survival. Subsequent optimization efforts led to the development of SR-C-107 (R), which exhibited strong activity against AML both at the cellular level (CC50(MOLM-13): 1.25 ± 0.18 μM; CC50(MV4-11): 0.81 ± 0.15 μM) and in vivo. These findings establish SR-C-107 (R) as a compelling candidate for AML treatment and lay the groundwork for the development of next-generation AML inhibitors.

Synthesis and Characterization of Thymol Carbon Nanodot Functionalized Silver Nanoparticles (ThCND-AgNPs) and Evaluation of Their Antiproliferative, Anti-Invasive, and Apoptotic Effects on OVCAR-3 Ovarian Cancer Cells.

Ovarian cancer belongs to the category of gynecological malignancies and unfortunately holds the distinction of being the most aggressive among them. It is ranked as the fifth highest cause of cancer-related deaths in women worldwide. The utilization of metal nanoparticles (NPs) linked with natural herbal molecules in biomedical applications has been on the rise. Thymol carbon nanodot functionalized silver nanoparticles (ThCND-AgNPs) were synthesized in an original manner and subjected to thorough characterization, including analysis of their size, morphology, and elemental composition. The aim of this study is to investigate the effects of the ThCND-AgNPs on cell proliferation, invasion, and apoptotic gene expressions in OVCAR-3 ovarian cancer cells. The effect of ThCND-AgNPs on cell viability in OVCAR cells was determined in a dose- and time-dependent manner using the XTT method. The effect on the expression changes of apoptotic-related genes was assessed through the Real-time PCR method, while the anti-invasive activity was measured using the matrigel invasion chamber assay. The ThCND-AgNP molecule exhibited a dose- and time-dependent reduction in cell proliferation in OVCAR-3 cells. The IC50 values were determined to be 388.53 μg/mL at 24 h and 145.683 μg/mL at 48 h. Furthermore, the molecule was found to reduce cell invasion by 51.12% compared with the control group in OVCAR-3 cells. In terms of apoptotic-related genes, Bcl-2 expression was downregulated, while BAX, CASPASE-3, -8, and -9 expressions were unregulated. In conclusion, the obtained data reveal the potential antiproliferative, apoptotic, and anti-invasive effects of our original ThCND-AgNP molecule in ovarian cancer. While these results need further confirmation through more detailed experiments, they will provide insights for future studies.

Synergistic effect of the sphingosine kinase inhibitor safingol in combination with 2'-nitroflavone in breast cancer.

Sphingosine kinase-1 (SPHK1), the enzyme that catalyzes the synthesis of the pro-oncogenic molecule sphingosine-1-phosphate, is commonly upregulated in breast cancer cells and has been linked with poor prognosis and progression by promoting cell transformation, proliferation, angiogenesis, and metastasis. Therefore, SPHK1-targeting drugs have been proposed for breast cancer treatment, with better antitumor results when they are combined with chemotherapy. Previously, we demonstrated that the synthetic flavonoid 2'-nitroflavone (2'NF) exerted a potent and selective antiproliferative effect in murine HER2-positive LM3 mammary tumor cells. As we found that these cells overexpress SPHK1, we decided to explore the antitumor action of the combination of SPHK inhibitors (safingol or SKI-II) with 2'NF. In vitro assays showed that the combination induced a synergistic antiproliferative effect in LM3 cells. Similar results were obtained when human HER2-positive MDA-MB-453 breast cancer cells were treated with the combination of 2'NF/safingol. We also found that safingol potentiated the 2'NF apoptotic effect in both cell lines. The synergistic antitumor effect was confirmed in vivo in an LM3 syngeneic breast cancer model. Moreover, western blot analysis of tumor lysates revealed that combined treatment increased PARP cleavage and Bax protein levels and decreased anti-apoptotic Bcl-xL and Bcl-2 protein levels. Additionally, mice treated with both compounds showed no histopathological effects on different organ tissues. In summary, these findings suggest that the combination safingol/2'NF can be proposed as a potential therapeutic strategy for HER2-positive breast cancer treatment. KEY MESSAGES: The combination safingol/2'-nitroflavone exerts a synergic antitumor action in vitro. Safingol potentiates 2'-nitroflavone apoptotic effect in breast cancer cells. Safingol enhances the 2'-nitroflavone antitumor activity in vivo in breast cancer.

Investigating the in vitro Anticancer Potential and Phytochemical Constituents of Cheilanthes hirta Swartz Plant Extracts

Cancer, a complex group of diseases characterized by uncontrolled cell growth, remains a leading cause of death worldwide, accounting for approximately 10 million deaths in 2020. Despite advancements in chemotherapy and targeted therapies, survival rates have not significantly improved, necessitating the exploration of novel anticancer agents. This study investigates the in vitro anticancer potential and phytochemical constituents of Cheilanthes hirta Swartz, a fern known for its medicinal properties. The plant was collected from KwaZulu Natal, South Africa and extracts were prepared using water, ethanol and methanol. The phytochemical and FTIR screening were carried out using standard procedure and anticancer activities of the extracts were assessed against prostate (PC-3 and DU-145), human T-lymphocytes (SKU-T) and gastric (AGS) cancer cell lines using the MTT assay. The phytochemical screening revealed the presence of tannins, terpenoids, saponins, flavonoids, cardiac glycosides, anthraquinones, phlobatannins, alkaloids and steroids. FTIR spectroscopy identified the functional groups such as hydroxyl, carboxylic acid, terminal alkynes, ketones, phenols and phosphate ions. The cytotoxicity results showed that the ethanol extract exhibited the most potent antiproliferative effects on prostate cancer cell lines, while the aqueous extract had the strongest effect on the gastric cancer cells. This study highlights the potential of C. hirta as a source of bioactive compounds for anticancer drug development, however, further investigation into its mechanisms of action and therapeutic efficacy is needed.

Enhanced Delivery and Potency of Chemotherapeutics in Melanoma Treatment via Magnetite Nanobioconjugates.

Melanoma, known for its aggressive metastatic potential, poses significant treatment challenges. Despite the potent antiproliferative effects of anticancer drugs, systemic toxicity and low water solubility limit their efficacy. This study addresses these challenges by employing magnetite (Fe3O4) nanobioconjugates as a drug delivery system, aimed at enhancing drug solubility and reducing off-target effects in melanoma therapy. Magnetite nanoparticles (MNPs) were engineered with functional molecules and loaded with the anticancer agents Temozolomide (TMZ) or paclitaxel (PTX). The nanobioconjugates were characterized via Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), dynamic light scattering (DLS), and transmission electron microscopy (TEM). The results validated the efficacious synthesis and drug loading, attaining efficiencies ranging from 32 to 72% for TMZ and 32 to 60% for PTX. Biocompatibility assessments demonstrated excellent tolerance, with minimal hemolysis rates and platelet aggregation. In vitro studies revealed enhanced cytotoxicity against A-375 human melanoma cells compared to free drugs, with cellular uptake facilitated primarily through macropinocytosis, caveolin-, and clathrin-mediated endocytosis. Furthermore, the nanobioconjugates exhibited significant efficacy in targeting A-375 melanoma spheroids, underlining their potential in melanoma therapy. This research underscores magnetite nanobioconjugates as a promising avenue for targeted melanoma treatment, offering enhanced drug delivery specificity and reduced systemic toxicity in oncological drug delivery systems.

Investigating the Mechanisms of Anti-tumoral Effect of Combination Therapy of Calcitriol and Sodium Pentaborate Pentahydrate on HepG2 Hepatocellular Carcinoma Cells.

Hepatocellular carcinoma (HCC) is one of the most common primary liver cancers worldwide and is often associated with poor prognosis due to drug resistance. Combination therapies demonstrate superior efficacy at lower drug dosages on cancer cells compared to single treatments, resulting in less drug resistance in the cells. This study investigates the synergistic anti-tumoral effects of calcitriol, the biologically active form of vitamin D, and sodium pentaborate pentahydrate (NaB) on HepG2 cells. We examined the cell viability of NaB, calcitriol, or the combination of NaB and calcitriol on HepG2 cells and healthy human hepatic stellate cells (HHSC) using MTS. Our findings showed that combination therapy with 3.3mM NaB and 1µM calcitriol has a synergistic effect and a more cytotoxic effect on HepG2 cells. This combination significantly increased apoptosis and ROS levels compared to treatment alone with NaB or calcitriol. Gene expression and proteomics analysis revealed inhibition of DNA replication and the cell cycle process, further confirming the potent anti-proliferative effects of the combination therapy. When HepG2 cells were treated with a combination of 3.3mM NaB and 1µM calcitriol, mRNA levels of apoptosis-related genes AKT1 and MDM2 were downregulated, while p53 was upregulated. Additionally, cell cycle-related genes CDKN1A, GADD45A, and p27 were upregulated, whereas MCM2, MCM5, and MCM7 were downregulated. Furthermore, genes associated with the vitamin D receptor (VDR), including VDR and CYP24A1, were upregulated, while CYP27B1 was downregulated. Our proteomic analysis revealed decreased MCM2 and MCM5 protein expressions which was confirmed by western blotting. In conclusion, this study highlights the potential of NaB and calcitriol as a promising therapeutic strategy for HCC.

Anti-Proliferative and Anti-Migratory Activity of Licorice Extract and Glycyrrhetinic Acid on Papillary Thyroid Cancer Cell Cultures

Papillary thyroid cancer (PTC) is the 8th most common cancer among women overall. Licorice contains over 300 active compounds, many of them with anti-cancer properties. Glycyrrhetinic acid (GA) is a major component of licorice. The aim of this study was to investigate the potential anti-proliferative effects of licorice and GA on PTC cell cultures. Licorice extract (LE) was produced from the root and tested on BCPAP and K1 cell lines, as well as GA and aldosterone. We used the MTT test to investigate the anti-proliferative activity, the wound healing test for the migratory activity, and finally, we analyzed cell cycle distribution, apoptosis, and oxidative stress after LE, GA, or aldosterone incubation. Both LE and GA reduced cell viability at 48 h and cell migration at 24 h in both PTC cultures. Aldosterone reduced cell migration only in K1 cells. LE and GA induced cell cycle arrest in the G0/G1 phase in the BCPAP cell line, while LE and aldosterone induced it in the K1 culture. GA but not LE increased the apoptosis rate in both cell lines, whereas LE but not GA increased oxidative stress in both cultures. This study presents the first evidence of the in vitro anti-proliferative and anti-migratory activity of LE and GA on PTC.