Unlocking daidzein's healing power: Present applications and future possibilities in phytomedicine.

BACKGROUND: Cancer is one of the leading causes of death and a great threat to people around the world. Cancer treatment modalities include surgery, radiotherapy, chemotherapy, radiochemotherapy, hormone therapy, and immunotherapy. The best approach is to use a combination of several types. Among the treatment methods mentioned above, chemotherapy is frequently used, but its activity is hampered by the development of drug resistance and many side effects. In this regard, the use of medicinal plants has been discussed, and in recent decades, the use of isolated phytochemicals came into the focus of interest. By critically evaluating the available evidence and emphasizing the unique perspective offered by this review, we provide insights into the potential of daidzein as a promising therapeutic agent, as well as outline future research directions to optimize its efficacy in clinical settings. PURPOSE: To summarized the therapeutic potential of daidzein, an isoflavone phytoestrogen in the management of several human diseases with the focuses on the current status and future prospects as a therapeutic agent. METHODS: Several search engines, including PubMed, GoogleScholar, and ScienceDirect, were used, with the search terms "daidzein", "daidzein therapeutic potential", or individual effects. The study included all peer-reviewed articles. However, the most recent publications were given priority. RESULTS: Daidzein showed protective effects against malignant diseases such as breast cancer, prostate cancer but also non-malignant diseases such as diabetes, osteoporosis, and cardiovascular diseases. Daidzein activates multiple signaling pathways leading to cell cycle arrest and apoptosis as well as antioxidant and anti-metastatic effects in malignant cells. Moreover, the anticancer effects against different cancer cells were more prominent and discussed in detail. CONCLUSIONS: In short, daidzein represents a promising compound for drug development. The comprehensive potential anticancer activities of daidzein through various molecular mechanisms and its therapeutic/clinical status required further detail studies.

Stable laminar shear stress induces G1 cell cycle arrest and autophagy in urothelial carcinoma by a torque sensor-coupled cone-and-plate device.

The microenvironments of urinary systems play crucial roles in the development and metastasis of cancers due to their generation of complex temporal and spatial fluidic profiles. Because of their versatility in creating desired biomimetic flow, cone-and-plate bioreactors offer great potential for bladder cancer research. In this study, we construct a biocompatible cone-and-plate device coupled with a torque sensor, enabling the application and real-time monitoring of stable shear stress up to 50 dyne/cm². Under a stable shear stress stimulation at 12 dyne/cm2, bladder cancer cell BFTC-905 is arrested at the G1 phase with decreased cell proliferation after 24-hour treatment. This effect is associated with increased cyclin-dependent kinase inhibitors p21 and p27, inhibiting cyclin D1/CDK4 complex with dephosphorylation of serine 608 on the retinoblastoma protein. Consequently, an increase in cyclin D3 and decreases in cyclin A2 and cyclin E2 are observed. Moreover, we demonstrate that the shear stress stimulation upregulates the expression of autophagy-related proteins Beclin-1, LC3B-I and LC3B-II, while caspase cleavages are not activated under the same condition. The design of this system and its application shed new light on flow-induced phenomena in the study of urothelial carcinomas.

Eslicarbazepine induces apoptosis and cell cycle arrest in C6 glioma cells in vitro and suppresses tumor growth in an intracranial rat model.

BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant brain tumor, with a poor prognosis and life expectancy of 14-16 months after diagnosis. The standard treatment for GBM consists of surgery, radiotherapy, and chemotherapy with temozolomide. Most patients become resistant to treatment after some time, and the tumor recurs. Therefore, there is a need for new drugs to manage GBM. Eslicarbazepine (ESL) is a well-known antiepileptic drug belonging to the dibenzazepine group with anticancer potentials. In this study, for the first time, we evaluated the potential effects of ESL on C6 cell growth, both in vitro and in vivo, and examined its molecular effects. METHODS: To determine the effect of ESL on the c6 cell line, cell viability, proliferation, and migration were evaluated by MTT assay, colony formation, and wound healing assay. Also, apoptosis and cell cycle were examined by flow cytometry, qRT-PCR, and western blotting. In addition, an intracranial model in Wistar rats was used to investigate the effect of ESL in vivo, and the tumor size was measured using both Caliper and MRI. RESULTS: The obtained results are extremely consistent and highly encouraging. C6 cell viability, proliferation, and migration were significantly suppressed in ESL-treated C6 cells (p < 0.001), as determined by cell-based assays. ESL treatment led to significant enhancement of apoptosis (p < 0.01), as determined by flow cytometry, and upregulation of genes involved in cell apoptosis, such as the Bax/Bcl2 ratio at RNA (p < 0.05) and protein levels (5.37-fold). Flow cytometric analysis of ESL-treated cells revealed G2/M phase cell cycle arrest. ESL-treated cells demonstrated 2.49-fold upregulation of p21 alongside, 0.22-fold downregulation of cyclin B1, and 0.34-fold downregulation of cyclin-dependent kinase-1 at the protein level. Administration of ESL (30 mg/kg) to male rats bearing C6 intracranial tumors also suppressed the tumor volume and weight (p < 0.01). CONCLUSIONS: Based on these novel findings, ESL has the potential for further experimental and clinical studies in glioblastoma.

LncRNA PTENP1/miR-21/PTEN Axis Modulates EMT and Drug Resistance in Cancer: Dynamic Boolean Modeling for Cell Fates in DNA Damage Response.

It is well established that microRNA-21 (miR-21) targets phosphatase and tensin homolog (PTEN), facilitating epithelial-to-mesenchymal transition (EMT) and drug resistance in cancer. Recent evidence indicates that PTEN activates its pseudogene-derived long non-coding RNA, PTENP1, which in turn inhibits miR-21. However, the dynamics of PTEN, miR-21, and PTENP1 in the DNA damage response (DDR) remain unclear. Thus, we propose a dynamic Boolean network model by integrating the published literature from various cancers. Our model shows good agreement with the experimental findings from breast cancer, hepatocellular carcinoma (HCC), and oral squamous cell carcinoma (OSCC), elucidating how DDR activation transitions from the intra-S phase to the G2 checkpoint, leading to a cascade of cellular responses such as cell cycle arrest, senescence, autophagy, apoptosis, drug resistance, and EMT. Model validation underscores the roles of PTENP1, miR-21, and PTEN in modulating EMT and drug resistance. Furthermore, our analysis reveals nine novel feedback loops, eight positive and one negative, mediated by PTEN and implicated in DDR cell fate determination, including pathways related to drug resistance and EMT. Our work presents a comprehensive framework for investigating cellular responses following DDR, underscoring the therapeutic potential of targeting PTEN, miR-21, and PTENP1 in cancer treatment.

Lupiwighteone as an Antitumor Agent Reverses Multidrug Resistance in K562/ADR Cells by Regulating Cellular Prion Protein-Oct4 Axis.

INTRODUCTION: One of the many reasons for cancer treatment failure and recurrence is acquired Multidrug Resistance (MDR). Overcoming cancer drug resistance has been the focus of researchers' studies. Cellular prion protein (PrPC) is a glycophosphatidylinositol-anchored cell-surface glycoprotein that has been implicated in tumor behavior, including proliferation, apoptosis, invasion, metastasis, and chemoresistance. >Method: Lupiwighteone (Lup), a natural isoflavone found in the root of Glycyrrhiza glabra, has anticancer activity against prostate cancer cells, neuroblastoma cells, and human breast cancer cells. However, its pharmacological effects and mechanisms in drug-resistant cancer cells have not been reported. In this study, we used an adriamycin- resistant leukemia K562 cell model, and for the first time, we investigated the reversal effect of Lup on its MDR and the potential mechanism. RESULT: The results indicated that Lup could induce apoptosis through the mitochondrial pathway while upregulating the expression of related apoptotic proteins, such as Bax, Cyto C, Caspase-3, and PARP1. Autophagy is commonly recognized as a protective mechanism that mediates MDR during treatment. We found that Lup induced cellular autophagy while upregulating the expression of related autophagy proteins such as Beclin 1 and LC3 II. CONCLUSION: In addition, when Lup was combined with adriamycin, Lup decreased the IC50 of K562/ADR cells; moreover, Lup can downregulate the expression of drug-resistant proteins, suggesting that Lup can reverse drug resistance. Further studies have shown that Lup can downregulate the expression of PrPC-PI3K-Akt axis proteins and PrPC-Oct4 axis proteins. This study demonstrated that Lup has the potential to inhibit the proliferation of K562/ADR cells by targeting PrPC, and further study of the signaling pathway associated with PrPC may provide the experimental basis for the treatment of drug-resistant leukemia.

Hyperglycemia-independent neonatal streptozotocin-induced retinopathy (NSIR) in rats.

Introduction: Chemicals, such as MNU (N-methyl-N-nitrosourea) and NaIO3 (sodium iodate), are widely used to induce retinal degeneration in rodents. Streptozotocin (STZ) is an analog of N-acetyl glucosamine in which an MNU moiety is linked to a hexose and has a special toxic effect on insulin-producing pancreatic ß-cells. It is commonly used to induce hyperglycemia to model diabetes. While intracerebroventricular injection of STZ can produce Alzheimer's disease independent of hyperglycemia, most retinal studies using STZ focus on the effects of hyperglycemia on the retina, but whether STZ has any impact on retinal cells independent of hyperglycemia is unknown. We aimed to investigate the role of cytotoxicity of STZ in rat retina. Methods: Intravitreal or subcutaneous injection of STZ was performed on newborn rats. Electroretinogram (ERG) and H&E staining investigated retinal function and morphological changes. Retinal cell types, cell death, proliferation, inflammation, and angiogenesis were studied by immunostaining. RNA sequencing was performed to examine the transcriptome changes of retinal cells after intravitreal injection of STZ. Results: Intravitreal (5 µg or 10 µg) or subcutaneous (30 mg/kg) injection of STZ at the early stage of newborn rats couldn't induce hyperglycemia but caused NSIR (Neonatal STZ-induced retinopathy), including reduced ERG amplitudes, retinal rosettes and apoptosis, cell cycle arrest, microglial activation, and delayed retinal angiogenesis. STZ did not affect the early-born retinal cell types but significantly reduced the late-born ones. Short-term and long-term hyperglycemia had no significant effects on the NSIR phenotypes. RNA sequencing revealed that STZ induces oxidative stress and activates the p53 pathway of retinal cells. Locally or systemically, STZ injection after P8 couldn't induce SINR when all retinal progenitors exit the cell cycle. Conclusion: NSIR in rats is independent of hyperglycemia but due to STZ's direct cytotoxic effects on retinal progenitor cells. NSIR is a typical reaction to STZ-induced retinal oxidative stress and DNA damage. This significant finding suggests that NSIR may be a valuable model for studying retinal progenitor DNA damage-related diseases, potentially leading to new insights and treatments.

Lycorine (Lycoris radiata)-a unique natural medicine on breast cancer.

Breast cancer (BC) is one of the most common types of cancer among women worldwide. Lycorine (Lycoris radiata), a small molecule derived from the traditional Chinese herb Amaryllidaceae plants, has appeared potential effect on inhibiting the growth of cancer cells and inducing apoptosis in various types of cancer with minor side effects. To discuss the therapeutic effects and molecular mechanisms of lycorine on BC established by lycorine-treated S180 tumour-bearing mice in vivo. Furthermore, both the mitotic and microtubule assembly dynamics genes were performed by qPCR assays, and the protein expression associated with mitotic arrest was investigated by western blot. Lycorine was demonstrated to reduce sarcoma growth of S180 tumour-bearing mice and inhibit the proliferation of MCF-7 cells in concentration-dependent manner. Moreover, lycorine induced M phase cell cycle arrest via interfering with the mitotic apparatus regulated the expression of 20 genes and 15 proteins in cell cycle progression. Furthermore, this study confirmed that the potential effect of lycorine on BC might be mediated by cell cycle arrest in M phase for the first time. These results would be the consequence of exploitation of lycorine as a potential drug for BC therapy, however further preclinical and clinical studies are still needed.

Mouse models to investigate in situ cell fate decisions induced by p53.

Investigating how transcription factors control complex cellular processes requires tools that enable responses to be visualised at the single-cell level and their cell fate to be followed over time. For example, the tumour suppressor p53 (also called TP53 in humans and TRP53 in mice) can initiate diverse cellular responses by transcriptional activation of its target genes: Puma to induce apoptotic cell death and p21 to induce cell cycle arrest/cell senescence. However, it is not known how these processes are regulated and initiated in different cell types. Also, the context-dependent interaction partners and binding loci of p53 remain largely elusive. To be able to examine these questions, we here developed knock-in mice expressing triple-FLAG-tagged p53 to facilitate p53 pull-down and two p53 response reporter mice, knocking tdTomato and GFP into the Puma/Bbc3 and p21 gene loci, respectively. By crossing these reporter mice into a p53-deficient background, we show that the new reporters reliably inform on p53-dependent and p53-independent initiation of both apoptotic or cell cycle arrest/senescence programs, respectively, in vitro and in vivo.

Artesunate induces HO-1-mediated cell cycle arrest and senescence to protect against ocular fibrosis.

Recent research found artesunate could inhibit ocular fibrosis; however, the underlying mechanisms are not fully known. Since the ocular fibroblast is the main effector cell in fibrosis, we hypothesized that artesunate may exert its protective effects by inhibiting the fibroblasts proliferation. TGF-ß1-induced ocular fibroblasts and glaucoma filtration surgery (GFS)-treated rabbits were used as ocular fibrotic models. Firstly, we analyzed fibrosis levels by assessing the expression of fibrotic marker proteins, and used Ki67 immunofluorescence, EdU staining, flow cytometry to determine cell cycle status, and SA-ß-gal staining to assess cellular senescence levels. Then to predict target genes and pathways of artesunate, we analyzed the differentially expressed genes and enriched pathways through RNA-seq. Western blot and immunohistochemistry were used to detect the pathway-related proteins. Additionally, we validated the dependence of artesunate's effects on HO-1 expression through HO-1 siRNA. Moreover, DCFDA and MitoSOX fluorescence staining were used to examine ROS level. We found artesunate significantly inhibits the expression of fibrosis-related proteins, induces cell cycle arrest and cellular senescence. Knocking down HO-1 in fibroblasts with siRNA reverses these regulatory effects of artesunate. Mechanistic studies show that artesunate significantly inhibits the activation of the Cyclin D1/CDK4-pRB pathway, induces an increase in cellular and mitochondrial ROS levels and activates the Nrf2/HO-1 pathway. In conclusion, the present study identifies that artesunate induces HO-1 expression through ROS to activate the antioxidant Nrf2/HO-1 pathway, subsequently inhibits the cell cycle regulation pathway Cyclin D1/CDK4-pRB in an HO-1-dependent way, induces cell cycle arrest and senescence, and thereby resists periorbital fibrosis.

Intracellular Survival and Pathogenicity Modulation of Salmonella Lon, CpxR, and RfaL Mutants Used as Live Bacterial Vectors under Abiotic Stress, Unveiling the Link between Stress Response and Virulence in Epithelial Cells.

In the current study, two Salmonella Typhimurium strains, JOL 912 and JOL 1800, were engineered from the wild-type JOL 401 strain through in-frame deletions of the lon and cpxR genes, with JOL 1800 also lacking rfaL. These deletions significantly attenuated the strains, impairing their intracellular survival and creating unique immunological profiles. This study investigates the response of these strains to various abiotic stress conditions commonly experienced in vivo, including temperature, acidity, osmotic, and oxidative stress. Notably, cold stress induced a non-significant trend towards increased invasion by Salmonella compared to other stressors. Despite the observed attenuation, no significant alterations in entry mechanisms (trigger vs. zipper) were noted between these strains, although variations were evident depending on the host cell type. Both strains effectively localized within the cytoplasm, demonstrating their ability to invade and interact with the intracellular environment. Immunologically, JOL 912 elicited a robust response, marked by substantial activation of nuclear factor kappa B (NF-kB), and chemokines, interleukin 8 (CXCL 8) and interleukin 10 (CXCL 10), comparable to the wild-type JOL 401 (over a fourfold increase compared to JOL 1800). In contrast, JOL 1800 exhibited a minimal immune response. Additionally, these attenuations influenced the expression of cyclins D1 and B1 and caspases 3 and 7, indicating cell cycle arrest at the G2/M phase and promotion of the G0/G1 to S phase transition, alongside apoptosis in infected cells. These findings provide valuable insights into the mechanisms governing the association, internalization, and survival of Salmonella mutants, enhancing our understanding of their regulatory effects on host cell physiology.

Targeting GLI1 and BAX by nanonoscapine could impede prostate adenocarcinoma progression.

Prostate cancer as a critical global health issue, requires the exploration of a novel therapeutic approach. Noscapine, an opium-derived phthalide isoquinoline alkaloid, has shown promise in cancer treatment thanks to its anti-tumorigenic properties. However, limitations such as low bioavailability and potential side effects have hindered its clinical application. This study introduces nanonoscapine as a novel medication to overcome these challenges, leveraging the advantages of improved drug delivery and efficacy achieved in nanotechnology. We monitored the effects of nanonoscapine on the androgen-sensitive human prostate adenocarcinoma cell line, LNCaP, investigating its impact on GLI1 and BAX genes' expressions, crucial regulators of cell cycle and apoptosis. Our findings, from MTT assays, flow cytometry, and gene expression analyses, have demonstrated that nanonoscapine effectively inhibits prostate cancer cell proliferation by inducing G2/M phase arrest and apoptosis. Furthermore, through bioinformatics and computational analyses, we have revealed the underlying molecular mechanisms, underscoring the therapeutic potential of nanonoscapine in enhancing patient outcomes. This study highlights the significance of nanonoscapine as an alternative or adjunct treatment to conventional chemotherapy, warranting further investigation in clinical settings.

Niacinamide Antimicrobial Efficacy and Its Mode of Action via Microbial Cell Cycle Arrest.

Niacinamide is a versatile compound widely used in the personal care industry for its ample skin benefits. As a precursor to nicotinamide adenine dinucleotide (NAD+), essential for ATP production and a substrate for poly-ADP-ribose polymerase-1 (PARP-1), studies have highlighted its roles in DNA repair, cellular stress mechanisms, and anti-aging benefits. Niacinamide was also studied for its antimicrobial activity, particularly in the context of host-infection via host immune response, yet its direct antimicrobial activity and the mechanisms of action remain unclear. Its multifunctionality makes it an appealing bioactive molecule for skincare products as well as a potential preservative solution. This study explores niacinamide's antimicrobial mode of action against four common cosmetic pathogens. Our findings indicate that niacinamide is causing microbial cell cycle arrest; while cells were found to increase their volume and length under treatment to prepare for cell division, complete separation into two daughter cells was prevented. Fluorescence microscopy revealed expanded chromatin, alongside a decreased RNA expression of the DNA-binding protein gene, dps. Finally, niacinamide was found to directly interact with DNA, hindering successful amplification. These unprecedented findings allowed us to add a newly rationalized preservative facete to the wide range of niacinamide multi-functionality.

In vitro cytotoxicity screening of some 3-substituted-4-oxo-imidazolidin-2-(1H)-thione derivatives as anticancer drug.

Aim: This study aimed to investigate the in vitro antitumor activity of new series of 2-thiohydanotin derivatives (7 and 9) against two cancer cell lines.Materials & methods: A new series of 2-thioxoimidazolidine derivatives (3-9) were synthesized and investigated for its structure through spectral analysis and also tested against (HepG-2) and (HCT-116) cell line.Results: Among the synthesized compounds, compound 7 halted liver cancer cells at the G0/G1 phase and triggered apoptosis of liver cancer. Contrarily, compound 9 caused colon cancer cells to be arrested at the S phase and trigger apoptosis. Also, they had a good inhibitory effect on (Nrf2).Conclusion: Both compounds had attractive lead molecules for the creation of colon and liver cancer medications.

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Mutant P53 modulation by cryptolepine through cell cycle arrest and apoptosis in triple negative breast cancer.

BACKGROUND: Triple Negative Breast cancer is an aggressive breast cancer subtype. It has a more aggressive clinical course, an earlier age of onset, a larger propensity for metastasis, and worse clinical outcomes as evidenced by a higher risk of recurrence and a shorter survival rate. Currently, the primary options for TNBC treatment are surgery, radiation, and chemotherapy. These treatments however remain ineffective due to recurrence. However, given that p53 mutations have been identified in more than 60-88 % of TNBC, translating p53 into the clinical situation is particularly important in TNBC. In this study, we screened and evaluated the therapeutic potential of cryptolepine (CRP) in TNBC in-vitro models being an anti-malarial drug it could be repurposed as an anti-cancer therapeutic targeting TNBC. Moreover, the cytotoxicity activity of cryptolepine to TNBC cells and a detailed anti-tumor mechanism in mutant P53 has not been reported before. METHODS: MTT assays were used to examine the cytotoxicity and cell viability activity of Cryptolepine in TNBC, non-TNBC T47D and MCF-7 and non-malignant MCF10A cells. Scratch wound and clonogenic assay was used to evaluate the cryptolepine's effect on migration and colony forming ability of TNBC cells. Flow cytometry, MMP and DAPI was used to assess cell cycle arrest and cell apoptosis mechanism. The expression of proteins was detected by western blots. The differential expression of RNAs was evaluated by RT-PCR and the interaction between P53 and drug was evaluated computationally using in-silico approach and in-vitro using ChIP assay. RESULTS: In this study, we found that cryptolepine has more preferential cytotoxicity in TNBC than non-TNBC cells. Notably, our studies revealed the mechanism by which cryptolepine induces intrinsic apoptosis and inhibit migration, colony formation ability, induce cell cycle arrest by inducing conformational change in the mutant P53 thereby increasing its DNA binding ability, hence activating its tumor suppressing potential significantly. CONCLUSION: Our study revealed that CRP significantly reduced the proliferation, migration and colony forming ability of TNBC cells lines. Moreover, it was revealed that CRP induces cell cycle arrest and apoptosis by activating mutant P53 and enhancing its DNA binding ability to induce its tumor suppressing ability.

TTI-101 targets STAT3/c-Myc signaling pathway to suppress cervical cancer progression: an integrated experimental and computational analysis.

BACKGROUND: Cervical cancer (CC) is a significant global health concern, demanding the consideration of novel therapeutic strategies. The signal transducer and activator of transcription 3 (STAT3) pathway has been implicated in cancer progression and is a potential target for therapeutic intervention. This study aimed to explore the therapeutic potential of TTI-101, a small molecule STAT3 inhibitor, in CC and investigate its underlying mechanisms. METHODS: Molecular docking studies and molecular dynamics simulations were performed to explore the binding interaction between TTI-101 and STAT3 and assess the stability of the STAT3-TTI-101 complex. Cell viability assays, wound healing assays, colony formation assays, flow cytometry analysis, and gene expression analysis were conducted. In vivo xenograft models were used to assess the antitumor efficacy of TTI-101. RESULTS: The in silico analysis shows a stable binding interaction between TTI-101 and STAT3. TTI-101 treatment inhibits cell viability, clonogenic ability, and cell migration in CC cells. Furthermore, TTI-101 induces apoptosis and cell cycle arrest. Analysis of apoptosis-related markers demonstrated dysregulation of Bax, Bcl-2, and Caspase-3 upon TTI-101 treatment. Moreover, TTI-101 caused G2/M phase arrest accompanied by a decrease in CDK1 and Cyclin B1 at mRNA levels. In the xenograft model, TTI-101 significantly inhibited tumor growth without adverse effects on body weight. CONCLUSION: TTI-101 exhibited anticancer effects by targeting the STAT3/c-Myc signaling pathway, inducing cell cycle arrest, and promoting apoptosis in CC cells. These findings provide valuable insights into the development of novel therapeutic strategies for cervical cancer. Further investigation is warranted to validate the clinical application of TTI-101.

Polycyclic polyprenylated acylphloroglucinols from the pericarps of Garcinia multiflora champ. ex Benth. with cytotoxic property.

The phytochemical investigation on the pericarps of Garcinia multiflora resulted in the isolation of 12 previously undescribed polycyclic polyprenylated acylphloroglucinols (PPAPs, 1-12) with a variety of skeletons. Their structures were determined by comprehensive spectroscopic analyses, ECD calculations, and single-crystal X-ray diffraction. Compounds 6-9 possess a rare bicyclo[4.3.1]decane skeleton. Additionally, the anti-tumor activity of the 12 isolates was evaluated. The results indicated that compounds 5, 9, and 12 exhibited significant cytotoxicity in a wide range of cancer cell lines, including the human breast cancer MDA-MB-231 cells, human lung cancer A549 cells, human colon cancer SW480 cells and human ovarian cancer HEY cells. Further studies indicated that compound 5 induced cell cycle arrest and apoptosis, to inhibit the growth of MDA-MB-231 cells. Taken together, these findings expand the chemical diversity of PPAPs and further demonstrate the potential of PPAPs as candidates for cancer treatment.

Molecular insights into epoxyazadiradione induced death in triple-negative breast cancer cells: A system biology approach.

Epoxyazadiradione is an important limonoid with immense pharmacological potential. We have reported previously that epoxyazadiradione (EAD) induces apoptosis in triple negative breast cancer cells (MDA-MB 231) by modulating diverse cellular targets. Here, we identify the key genes/pathways responsible for this effect through next-generation sequencing of the transcriptome from EAD treated cells and integrated molecular data analysis using bioinformatics. In silico analysis indicated that EAD displayed favourable drug-like properties and could target multiple macromolecules relevant to TNBC. RNA sequencing revealed that EAD treatment results in the differential expression of 1838 genes in MDA-MB 231 cells, with 752 downregulated and 1086 upregulated. Gene set enrichment analysis of these genes suggested that EAD disrupts protein folding in the endoplasmic reticulum, triggering the unfolded protein response (UPR) and potentially leading to cell death. EAD also induced oxidative stress and DNA damage, downregulated pathways linked to metabolism, cell cycle progression, pro-survival signalling, cell adhesion, motility and inflammatory response. The identification of protein cluster and hub genes were also done. The validation of the identified hub genes gave an inverse correlation between their expression in EAD treated cells and TNBC patient samples. Thus, the identified hub genes could be explored as therapeutic or diagnostic markers for TNBC. Hence, EAD appears to be a promising therapeutic candidate for TNBC by targeting various hallmarks of cancer, including cell death resistance, uncontrolled proliferation and metastasis. To conclude, the identified pathways and validated targets for EAD will provide a roadmap for further in vivo studies and preclinical/clinical validation required for potential drug development.

10-Eicosanol Alleviates Patulin-Induced Cell Cycle Arrest and Apoptosis by Activating AKT (Protein Kinase B) in Porcine Intestinal Epithelial Cells.

Patulin (PAT) is a fungal toxin prevalent in apples and apple products and associated with several toxic effects, potentially harming multiple organs, including the kidneys, liver, and colon. However, the precise molecular mechanism through which PAT affects the intestines remains comprehensively unclear. Therefore, this study aims to investigate the molecular effects of PAT on the intestinal epithelium. Gene expression profiling was conducted, hypothesizing that PAT induces cell cycle arrest and apoptosis through the PI3K-Akt signaling pathway. Cell cycle analysis, along with Annexin-V and propidium iodide staining, confirmed that PAT induced G2/M phase arrest and apoptosis in IPEC-J2 cells. Additionally, PAT activated the expression of cell cycle-related genes (CDK1, CCNB1) and apoptosis-related genes (BCL6, CASP9). Treatment with SC79, an AKT activator, mitigated cell cycle arrest and apoptosis. To identify natural products that could mitigate the harmful effects of PAT in small intestinal epithelial cells in pigs, the high-throughput screening of a natural product library was conducted, revealing 10-Eicosanol as a promising candidate. In conclusion, our study demonstrates that 10-Eicosanol alleviates PAT-induced cell cycle arrest and apoptosis in IPEC-J2 cells by activating AKT.

Novel Antimitotic Agent SP-1-39 Inhibits Head and Neck Squamous Cell Carcinoma.

Effective management of head and neck cancer (HNC) poses a significant challenge in the field of oncology, due to its intricate pathophysiology and limited treatment options. The most common HNC malignancy is head and neck squamous cell carcinoma (HNSCC). HNSCC treatment includes a combination of surgery, radiation, and chemotherapy. While HNSCC is treatable if diagnosed early, this is often not the case and is considered incurable once in its late stages and metastatic disease has developed. Therapies are also limited once resistant disease has occurred. SP-1-39, a novel colchicine-binding site inhibitor (CBSI), has been recently reported for its potential efficacy in a variety of cancer cell lines including breast, melanoma, pancreatic, and prostate. SP-1-39 also shows abilities to overcome paclitaxel resistance in a paclitaxel-resistant prostate cancer xenograft model. To evaluate the potential of SP-1-39 as a new HNSCC treatment option, herein we systematically performed preclinical studies in HNSCC models using SP-1-39 and demonstrated that, in vitro, SP-1-39 inhibits the proliferation of 2 HNSCC cell lines with low nanomolar IC50 values (1.4 to 2.1 nM), induces HNSCC cell apoptosis in a dose-dependent manner, interferes with migration of HNSCC cells, and leads to HNSCC cell cycle arrest in the G2/M phase. In vivo, SP-1-39 suppresses the primary tumor growth of a Detroit 562 subcutaneous xenograft mouse model in 6- to 8-wk-old, male NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice, with no detectable cytotoxic effects at a low dose of 2.5 mg/kg. This efficacy of SP-1-39 is better when compared with the treatment using a reference chemotherapy drug, paclitaxel at 10 mg/kg. Collectively, these data demonstrate that SP-1-39 is a promising candidate for further development for more efficacious HNSCC treatment.

Bisdemethoxycurcumin Augments Docetaxel Efficacy for Treatment of Prostate Cancer.

Bisdemethoxycurcumin (BDMC) is one of major forms of curcuminoids found in the rhizomes of turmeric. Docetaxel (DTX) is the standard of care for men diagnosed with androgen-independent prostate cancers. Here we report for the first time that BDMC could reinforce the effect of DTX against prostate cancer in vitro and in vivo. In vitro study, PC3 and LNCaP cells were cultured and treated with BDMC and DTX alone or in combination. The effects on cell viability were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was assessed by annexin V/propidium iodide (PI) staining, while cell cycle was assessed by PI staining. Bax, Bcl-2, caspase, poly(ADP-ribose)polymerase (PARP), cyclin B1 and CDK1 expression were assayed by Western blot. We found that a combination treatment of BDMC (10 µM) with DTX (10 nM) was more effective in the inhibition of PC3 and LNCaP cell growth and induction of apoptosis as well as G2/M arrest, which is accompanied with the significant inhibition of Bcl-2, cyclin B1, CDK1 expression and significant increase of Bax, cleaved caspase-9, cleaved caspase-3 and cleaved PARP, than those by treatment of BDMC or DTX alone. Moreover, in vivo evaluation further demonstrated the superior anticancer efficacy of BDMC and DTX compared to DTX alone in a murine prostate cancer model. These results suggest that BDMC can be an attractive therapeutic candidate in enhancing the efficacy of DTX in prostate cancer treatment.