ABSTRACT
BACKGROUND AND AIMS: Artificial intelligence (AI) is increasingly used to improve adenoma detection during colonoscopy. This meta-analysis aimed to provide an updated evaluation of computer-aided detection (CADe) systems and their impact on key colonoscopy quality indicators. METHODS: We searched the Embase, PubMed and MEDLINE databases from inception until February 15, 2024, for randomised control trials (RCTs) comparing the performance CADe systems with routine unassisted colonoscopy in the detection of colorectal adenomas. RESULTS: 28 RCTs were selected for inclusion involving 23861 participants. Random-effects meta-analysis demonstrated a 20% increase in ADR (RR 1.20, 95% CI 1.14-1.27, p<0.01) and 55% decrease in AMR (RR 0.45, 95% CI 0.37-0.54, p<0.01) with AI-assisted colonoscopy. Subgroup analyses involving only expert endoscopists demonstrated a similar effect size (RR 1.19, 95% CI 1.11-1.27, p<0.001), with similar findings seen in analysis of differing CADe systems and healthcare settings. CADe use also significantly increased adenomas per colonoscopy (weighted mean difference 0.21, 95% CI 0.14-0.29, p<0.01), primarily due to increased diminutive lesion detection, with no significant difference seen in detection of advanced adenoma. Sessile serrated lesion detection (RR 1.10, 95% CI 0.93-1.30, p=0.27) and miss rates (RR 0.44, 95% CI 0.16-1.19, p=0.11) were similar. There was an average 0.15 minute prolongation of withdrawal time with AI-assisted colonoscopy (weighted mean difference 0.15, 95% CI 0.04-0.25, p = 0.01) and a 39% increase in the rate of non-neoplastic resection (RR 1.39, 95% CI 1.23-1.57, p<0.001). CONCLUSIONS: AI-assisted colonoscopy significantly improved adenoma, but not sessile serrated lesion, detection irrespective of endoscopist experience, system type or healthcare setting.
ABSTRACT
The application of extracellular vesicles, particularly exosomes (EXs), is rapidly expanding in the field of medicine, owing to their remarkable properties as natural carriers of biological cargo. This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues (NAF-EXs) for personalized medicine, which can be derived at the time of diagnosis by endoscopic ultrasound. Herein, we show that exosomes (EXs) derived from NAFs demonstrate differential bio-physical characteristics, efficient cellular internalization, drug loading efficiency, pancreatic tumor targeting and delivery of payloads. NAF-derived EXs (NAF-EXs) were used for loading ormeloxifene (ORM), a potent anti-cancer and desmoplasia inhibitor as a model drug. We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype, which may be due to regulation of Ca2+ influx in fibroblast cells. NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition (EMT) and repressed tumor growth in xenograft mouse model. In conclusion, our data suggests preferential tropism of NAF-EXs for PDAC tumors, thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs. Additionally, it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.
ABSTRACT
BACKGROUND: The management of inflammatory bowel disease [IBD] patients with concurrent liver transplantation is challenging, and data regarding the safety and efficacy of Janus kinase [JAK] inhibitors with anti-rejection medications are required. We report the experience of all liver transplant recipients receiving tofacitinib and/or upadacitinib for IBD across three states in Australia. METHODS: All liver transplant recipients from the Australian states of Victoria, New South Wales, and Tasmania, who required tofacitinib or upadacitinib for the treatment of IBD, were identified using prospectively maintained liver transplant databases. Patients were followed up until medication cessation or last follow-up. Clinical safety and efficacy data were collected. RESULTS: Eight patients [median age 30 years] were included, seven of whom received first-line JAK inhibition with tofacitinib. All patients had failed one or more biologic therapies prior to commencing JAK inhibition, including six patients who had failed two or more agents. JAK inhibition was continued for a median of 17 months, with 143 patient-months of combined follow-up. The anti-rejection medication tacrolimus was prescribed in all patients. Overall, seven [88%] patients achieved clinical remission, including all three patients who were switched from tofacitinib to upadacitinib. One patient required colectomy after 1 month of treatment. There were no other cases of serious infection, venous thromboembolism, or major adverse cardiovascular events during follow-up. CONCLUSIONS: As the largest case series to date, these data indicate that combining JAK inhibition with transplant anti-rejection medication may be a safe and clinically effective method of treating IBD in patients with prior biologic failure.
Subject(s)
Heterocyclic Compounds, 3-Ring , Inflammatory Bowel Diseases , Janus Kinase Inhibitors , Liver Transplantation , Piperidines , Pyrimidines , Humans , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Female , Male , Adult , Piperidines/therapeutic use , Piperidines/adverse effects , Pyrimidines/therapeutic use , Pyrimidines/adverse effects , Inflammatory Bowel Diseases/drug therapy , Middle Aged , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/adverse effects , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/adverse effects , Tacrolimus/therapeutic use , Tacrolimus/adverse effects , Australia , Treatment Outcome , Young Adult , Pyrroles/therapeutic use , Pyrroles/adverse effects , Pyrroles/administration & dosageABSTRACT
Anchorage-independent survival after intravasation of cancer cells from the primary tumor site represents a critical step in metastasis. Here, we reveal new insights into how MUC13-mediated anoikis resistance, coupled with survival of colorectal tumor cells, leads to distant metastasis. We found that MUC13 targets a potent transcriptional coactivator, YAP1, and drives its nuclear translocation via forming a novel survival complex, which in turn augments the levels of pro-survival and metastasis-associated genes. High expression of MUC13 is correlated well with extensive macrometastasis of colon cancer cells with elevated nuclear YAP1 in physiologically relevant whole animal model systems. Interestingly, a positive correlation of MUC13 and YAP1 expression was observed in human colorectal cancer tissues. In brief, the results presented here broaden the significance of MCU13 in cancer metastasis via targeting YAP1 for the first time and provide new avenues for developing novel strategies for targeting cancer metastasis.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Animals , Humans , Colorectal Neoplasms/metabolism , Transcription Factors/genetics , Mucins/metabolismABSTRACT
A highly stereo-selective, one-pot, multicomponent method was chosen to synthesize the novel functionalized 1, 3-cycloaddition spirooxindoles (SOXs) (4a-4h). Synthesized SOXs were analyzed for their drug-likeness and ADME parameters and screened for their anticancer activity. Our molecular docking analysis revealed that among all derivatives of SOXs (4a-4h), 4a has a substantial binding affinity (∆G) -6.65, -6.55, -8.73, and -7.27 Kcal/mol with CD-44, EGFR, AKR1D1, and HER-2, respectively. A functional study demonstrated that SOX 4a has a substantial impact on human cancer cell phenotypes exhibiting abnormality in cytoplasmic and nuclear architecture as well as granule formation leading to cell death. SOX 4a treatment robustly induced reactive oxygen species (ROS) generation in cancer cells as observed by enhanced DCFH-DA signals. Overall, our results suggest that SOX (4a) targets CD-44, EGFR, AKR1D1, and HER-2 and induces ROS generation in cancer cells. We conclude that SOX (4a) could be explored as a potential chemotherapeutic molecule against various cancers in appropriate pre-clinical in vitro and in vivo model systems.
Subject(s)
Antineoplastic Agents , Humans , Molecular Structure , Structure-Activity Relationship , Antineoplastic Agents/chemistry , Molecular Docking Simulation , Reactive Oxygen Species , ErbB Receptors/metabolismABSTRACT
Sunlight exposure is a significant risk factor for UV-induced deteriorating transformations of epidermal homeostasis leading to skin carcinogenesis. The ability of UVB radiation to cause melanoma, as well as basal and squamous cell carcinomas, makes UVB the most harmful among the three known UV ranges. UVB-induced DNA mutations and dysregulation of signaling pathways contribute to skin cancer formation. Among various signaling pathways modulated by UVB, tyrosine phosphorylation signaling which is mediated by the action of protein tyrosine kinases (PTKs) on specific tyrosine residues is highly implicated in photocarcinogenesis. Following UVB irradiation, PTKs get activated and their downstream signaling pathways contribute to photocarcinogenesis by promoting the survival of damaged keratinocytes and increasing cell proliferation. While UVB activates oncogenic signaling pathways, it can also activate tumor suppressive signaling pathways as initial protective mechanisms to maintain epidermal homeostasis. Tyrosine dephosphorylation is one of the protective mechanisms and is mediated by the action of protein tyrosine phosphatases (PTPs). PTP can counteract UVB-mediated PTK activation and downregulate oncogenic signaling pathways. However, PTPs have not been studied extensively in photocarcinogenesis with previous studies regarding their inactivation induced by UVB. This current review will summarize the recent progress in the protective function of PTPs in epidermal photocarcinogenesis.
Subject(s)
Skin Neoplasms , Ultraviolet Rays , Humans , Phosphorylation , Keratinocytes/radiation effects , Protein Tyrosine Phosphatases/metabolism , Carcinogenesis , Skin Neoplasms/etiology , Skin Neoplasms/metabolism , Tyrosine/metabolismABSTRACT
The UVB irradiation is well known for its impact on the development of skin cancer. However, low UVB irradiation plays a protective role against various human diseases including cancer through its effect on tumor suppression. This article summarizes the key findings of the paper by Park et al., which describes a novel molecular mechanism of moderate UVB irradiation in suppressing the growth of melanoma and colorectal cancer. Key observations in this article are that moderate UVB irradiation can enhance tumor immunity by (1) increased infiltration of CD4+ and CD8+ T cells; (2) increased infiltration of CD103+ conventional type 1 dendritic cells (cDC1); and (3) a significant decrease of M2 tumor associate macrophages (TAMs) into the tumor. The authors further identified the role of Batf3 transcription factor in moderate UVB irradiation-mediated anti-tumor immune response. Deletion of Batf3 transcription factor reversed the tumor suppressive effect with decreased CD103+ cDC1 cell infiltration. This pre-clinical study provides a very novel mechanistic insight into the utilization of moderate UVB irradiation for the management of melanoma and colorectal cancer. This study further provides the direction of new future research to explore moderate UVB irradiation in combination with checkpoint blockade antibodies to enhance immunotherapeutic response against various solid tumors.
Subject(s)
Colorectal Neoplasms , Melanoma , Skin Neoplasms , Humans , CD8-Positive T-Lymphocytes/pathology , Skin Neoplasms/pathology , Ultraviolet Rays , Transcription Factors , Colorectal Neoplasms/radiotherapyABSTRACT
There is increasing evidence suggesting the role of microbiome alterations in relation to pancreatic adenocarcinoma and tumor immune functionality. However, molecular mechanisms of the interplay between microbiome signatures and/or their metabolites in pancreatic tumor immunosurveillance are not well understood. We have identified that a probiotic strain (Lactobacillus casei) derived siderophore (ferrichrome) efficiently reprograms tumor-associated macrophages (TAMs) and increases CD8 + T cell infiltration into tumors that paralleled a marked reduction in tumor burden in a syngeneic mouse model of pancreatic cancer. Interestingly, this altered immune response improved anti-PD-L1 therapy that suggests promise of a novel combination (ferrichrome and immune checkpoint inhibitors) therapy for pancreatic cancer treatment. Mechanistically, ferrichrome induced TAMs polarization via activation of the TLR4 pathway that represses the expression of iron export protein ferroportin (FPN1) in macrophages. This study describes a novel probiotic based molecular mechanism that can effectively induce anti-tumor immunosurveillance and improve immune checkpoint inhibitors therapy response in pancreatic cancer.
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Probiotics , Mice , Animals , Pancreatic Neoplasms/therapy , Pancreatic Neoplasms/metabolism , Adenocarcinoma/metabolism , Siderophores , Tumor Microenvironment , Ferrichrome/therapeutic use , Monitoring, Immunologic , Immune Checkpoint Inhibitors , Probiotics/pharmacology , Pancreatic NeoplasmsABSTRACT
Multidrug resistance (MDR) is one of the major therapeutic challenges that limits the efficacy of chemotherapeutic response resulting in poor prognosis of ovarian cancer (OC). The multidrug resistance protein 1 (MRP1) is a membrane-bound ABC transporter involved in cross resistance to many structurally and functionally diverse classes of anticancer drugs including doxorubicin, taxane, and platinum. In this study, we utilize homology modelling and molecular docking analysis to determine the binding affinity and the potential interaction sites of MRP1 with Carboplatin, Gemcitabine, Doxorubicin, Paclitaxel, and Topotecan. We used AutoDock Vina scores to compare the binding affinities of the anticancer drugs against MRP1. Our results depicted Carboplatin < Gemcitabine < Topotecan < Doxorubicin < Paclitaxel as the order of binding affinities. Paclitaxel has shown the highest binding affinity whereas Carboplatin displayed the lowest affinity to MRP1. Interestingly, our data showed that Carboplatin, Paclitaxel, and Topotecan bind specifically to Asn510 residue in the transmembrane domains 1 of the MRP1. Our results suggest that Carboplatin could be an appropriate therapeutic choice against MRP1 in OC as it couples weakly with Carboplatin. Further, our findings also recommend opting Carboplatin with Gemcitabine as a combinatorial chemotherapeutic approach to overcome MDR phenotype associated with recurrent OC.
ABSTRACT
Tumor heterogeneity is a predominant feature of hepatocellular carcinoma (HCC) that plays a crucial role in chemoresistance and limits the efficacy of available chemo/immunotherapy regimens. Thus, a better understanding regarding the molecular determinants of tumor heterogeneity will help in developing newer strategies for effective HCC management. Chemokines, a sub-family of cytokines are one of the key molecular determinants of tumor heterogeneity in HCC and are involved in cell survival, growth, migration, and angiogenesis. Herein, we provide a panoramic insight into the role of chemokines in HCC heterogeneity at genetic, epigenetic, metabolic, immune cell composition, and tumor microenvironment levels and its impact on clinical outcomes. Interestingly, our in-silico analysis data showed that expression of chemokine receptors impacts infiltration of various immune cell populations into the liver tumor and leads to heterogeneity. Thus, it is evident that aberrant chemokines clouding impacts HCC tumor heterogeneity and understanding this phenomenon in depth could be harnessed for the development of personalized medicine strategies in future.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Liver Neoplasms/genetics , Liver Neoplasms/therapy , Liver Neoplasms/metabolism , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/metabolism , Chemokines/metabolism , Tumor Microenvironment/genetics , Neovascularization, PathologicABSTRACT
Pancreatic cancer has the worst prognosis and lowest survival rate among all cancers. Pancreatic cancer cells are highly metabolically active and typically reprogrammed for aberrant glucose metabolism; thus they respond poorly to therapeutic modalities. It is highly imperative to understand mechanisms that are responsible for high glucose metabolism and identify natural/synthetic agents that can repress glucose metabolic machinery in pancreatic cancer cells, to improve the therapeutic outcomes/management of pancreatic cancer patients. We have identified a glycoside, steviol that effectively represses glucose consumption in pancreatic cancer cells via the inhibition of the translation initiation machinery of the molecular components. Herein, we report that steviol effectively inhibits the glucose uptake and lactate production in pancreatic cancer cells (AsPC1 and HPAF-II). The growth, colonization, and invasion characteristics of pancreatic cancer cells were also determined by in vitro functional assay. Steviol treatment also inhibited the tumorigenic and metastatic potential of human pancreatic cancer cells by inducing apoptosis and cell cycle arrest in the G1/M phase. The metabolic shift by steviol was mediated through the repression of the phosphorylation of mTOR and translation initiation proteins (4E-BP1, eIF4e, eIF4B, and eIF4G). Overall, the results of this study suggest that steviol can effectively suppress the glucose metabolism and translation initiation in pancreatic cancer cells to mitigate their aggressiveness. This study might help in the design of newer combination therapeutic strategies for pancreatic cancer treatment.
ABSTRACT
Exosomes are nanoscale vesicles generated by cells for intercellular communication. Due to their composition, significant research has been conducted to transform these particles into specific delivery systems for various disease states. In this review, we discuss the common isolation and loading methods of exosomes, some of the major roles of exosomes in the tumor microenvironment, as well as discuss recent applications of exosomes as drug delivery vessels and the resulting clinical implications.
Subject(s)
Drug Delivery Systems/methods , Exosomes/metabolism , Neoplasms/therapy , Exosomes/pathology , Exosomes/physiology , Humans , Neoplasms/metabolism , Neoplasms/pathology , Tumor Microenvironment/drug effects , Tumor Microenvironment/physiologyABSTRACT
Age-related macular degeneration (AMD) is the leading cause of blindness in the industrialized world. AMD is associated with dysfunction and atrophy of the retinal pigment epithelium (RPE), which provides critical support for photoreceptor survival and function. RPE transplantation is a promising avenue towards a potentially curative treatment for early stage AMD patients, with encouraging reports from animal trials supporting recent progression toward clinical treatments. Mature RPE cells have been reported to be superior, but a detailed investigation of the specific changes in the expression pattern of key RPE genes during maturation is lacking. To understand the effect of maturity on RPE, we investigated transcript levels of 19 key RPE genes using ARPE-19 cell line and human embryonic stem cell-derived RPE cultures. Mature RPE cultures upregulated PEDF, IGF-1, CNTF and BDNF-genes that code for trophic factors known to enhance the survival and function of photoreceptors. Moreover, the mRNA levels of these genes are maximized after 42 days of maturation in culture and lost upon dissociation to single cells. Our findings will help to inform future animal and human RPE transplantation efforts.
Subject(s)
Gene Expression Regulation , Retinal Pigment Epithelium/cytology , Retinal Pigment Epithelium/physiology , Brain-Derived Neurotrophic Factor/genetics , Cell Culture Techniques , Cell Line , Cells, Cultured , Ciliary Neurotrophic Factor/genetics , Eye Proteins/genetics , Humans , Insulin-Like Growth Factor I/genetics , Nerve Growth Factors/genetics , Serpins/genetics , Time Factors , Up-RegulationABSTRACT
Pancreatic cancer (PanCa) is a highly lethal disease with a poor 5 year survival rate, less than 7%. It has a dismal prognosis, and more than 50% of cases are detected at an advanced and metastatic stage. Gemcitabine (GEM) is a gold standard chemotherapy used for PanCa treatment. However, GEM-acquired resistance in cancer cells is considered as a major setback for its continued clinical implementation. This phenomenon is evidently linked to de novo lipid synthesis. PanCa cells rely on de novo lipid synthesis, which is a prime event in survival and one of the key drivers for tumorigenesis, cancer progression, and drug resistance. Thus, the depletion of lipogenesis or lipid metabolism can not only improve treatment outcomes but also overcome chemoresistance, which is an unmet clinical need. Toward this effort, our study reports a unique paclitaxel-poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PPNPs) formulation which can target lipid metabolism and improve anticancer efficacy of GEM in PanCa cells. PPNPs inhibit excessive lipid formation and alter membrane stability with compromised membrane integrity, which was confirmed by Fourier transform infrared and zeta potential measurements. The effective interference of PPNPs in lipid metabolic signaling was determined by reduction in the expression of FASN, ACC, lipin, and Cox-2 proteins. This molecular action profoundly enhances efficacy of GEM as evident through enhanced inhibitory effects on the tumorigenic and metastasis assays in PanCa cells. These data clearly suggest that the ablation of lipid metabolism might offer an innovative approach for the improved therapeutic outcome in PanCa patients.
ABSTRACT
In this study, we investigated the therapeutic efficacy of VERU-111 in vitro and in vivo model systems of cervical cancer. VERU-111 treatment inhibited cell proliferation and, clonogenic potential, induce accumulation of p53 and down regulated the expression of HPV E6/E7 expression in cervical cancer cells. In addition, VERU-111 treatment also decreased the phosphorylation of Jak2(Tyr1007/1008) and STAT3 at Tyr705 and Ser727. VERU-111 treatment arrested cell cycle in the G2/M phase and modulated cell cycle regulatory proteins (cyclin B1, p21, p34cdc2 and pcdk1). Moreover, VERU-111 treatment induced apoptosis and modulated the expression of Bid, Bcl-xl, Survivin, Bax, Bcl2 and cleavage in PARP. In functional assays, VERU-111 markedly reduced the migratory and invasive potential of cervical cancer cells via modulations of MMPs. VERU-111 treatment also showed significant (P < 0.05) inhibition of orthotopic xenograft tumor growth in athymic nude mice. Taken together, our results demonstrate the potent anti-cancer efficacy of VERU-111 in experimental cervical cancer models.Thus, VERU-111 can be explored as a promising therapeutic agent for the treatment of cervical cancer.
Subject(s)
Benzimidazoles/pharmacology , Imidazoles/therapeutic use , Indoles/therapeutic use , Papillomavirus Infections/drug therapy , Signal Transduction/drug effects , Tumor Suppressor Protein p53/metabolism , Uterine Cervical Neoplasms/drug therapy , Animals , Benzimidazoles/therapeutic use , Female , HeLa Cells , Humans , Imidazoles/pharmacology , Indoles/pharmacology , Janus Kinase 2/metabolism , Mice , Papillomavirus E7 Proteins/antagonists & inhibitors , Papillomavirus E7 Proteins/metabolism , Papillomavirus Infections/pathology , Papillomavirus Infections/virology , Phosphorylation/drug effects , STAT3 Transcription Factor/metabolism , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/virology , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Cervical cancer (CxCa) ranks as the fourth most prevalent women-related cancer worldwide. Therefore, there is a crucial need to develop newer treatment modalities. Ormeloxifene (ORM) is a non-steroidal, selective estrogen receptor modulator (SERM) that is used as an oral contraceptive in humans. Recent investigations suggest that ORM exhibits potent anti-cancer activity against various types of cancers. Nanoparticulates offer targeted delivery of anti-cancer drugs with minimal toxicity and promise newer approaches for cancer diagnosis and treatment. Therefore, the nanotherapy approach is superior compared to traditional chemotherapy, which is not site-specific and is often associated with various side effects. METHODS: Pursuing this novel nanotherapy approach, our lab has recently developed ORM-loaded poly [lactic-co-glycolic acid] (PLGA), an FDA-approved biodegradable polymer, nanoparticles to achieve targeted drug delivery and improved bioavailability. Our optimized PLGA-ORM nanoformulation showed improved internalization in both dose- and energy-dependent manners, through endocytosis-mediated pathways in both Caski and SiHa cell lines. Additionally, we employed MTS and colony forming assays to determine the short- and long-term effects of PLGA-ORM on these cells. RESULTS: Our results showed that this formulation demonstrated improved inhibition of cellular proliferation and clonogenic potential compared to free ORM. Furthermore, the PLGA-ORM nanoformulation exhibited superior anti-tumor activities in an orthotopic cervical cancer mouse model than free ORM. CONCLUSION: Collectively, our findings suggest that our novel nanoformulation has great potential for repurposing the drug and becoming a novel modality for CxCa management.
Subject(s)
Benzopyrans/therapeutic use , Nanoparticles/therapeutic use , Uterine Cervical Neoplasms/drug therapy , Animals , Benzopyrans/pharmacology , Carcinogenesis/drug effects , Carcinogenesis/metabolism , Carcinogenesis/pathology , Cell Line, Tumor , Cell Membrane/drug effects , Cell Membrane/metabolism , Cell Proliferation/drug effects , Cell Survival/drug effects , Clone Cells , Disease Models, Animal , Endocytosis/drug effects , Erythrocytes/metabolism , Female , Hemolysis/drug effects , Humans , Materials Testing , Membrane Potential, Mitochondrial/drug effects , Mice, Nude , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Serum/chemistry , Uterine Cervical Neoplasms/pathologyABSTRACT
Selective estrogen receptor modulator drug molecules of triphenylethylene family have gained considerable attention as anti-cancer agents. Despite recent advances in screening and development of HPV vaccines, cervical cancer remains one of the deadliest malignancies as advanced stage metastatic disease is mostly untreatable, thus warrants newer therapeutic strategies. Ormeloxifene (ORM) is a well-known SERM of triphenylethylene family that has been approved for human use, thus represents an ideal molecule for repurposing. In this study, we for the first time have demonstrated the anti-cancerous properties of ormeloxifene in cervical cancer. Ormeloxifene efficiently attenuated tumorigenic and metastatic properties of cervical cancer cells via arresting cell cycle at G1-S transition, inducing apoptosis, decreasing PI3K and Akt phosphorylation, mitochondrial membrane potential, and modulating G1-S transition related proteins (p21, cyclin E and Cdk2). Moreover, ORM repressed the expression of HPV E6/ E7 oncoproteins and restored the expression of their downstream target tumor suppressor proteins (p53, Rb and PTPN 13). As a result, ormeloxifene induces radio-sensitization in cervical cancer cells and caused potent tumor growth inhibition in orthotopic mouse model. Taken together, ormeloxifene represents an alternative therapeutic modality for cervical cancer which may have rapid clinical translation as it is already proven safe for human use.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzopyrans/therapeutic use , Drug Repositioning , Uterine Cervical Neoplasms/drug therapy , Animals , Apoptosis/drug effects , Carcinogenesis/drug effects , Cell Line, Tumor , Female , G1 Phase Cell Cycle Checkpoints/drug effects , Humans , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Nude , Papillomavirus E7 Proteins/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Pancreatic cancer (PanCa) is a major cause of cancer-related death due to limited therapeutic options. As pancreatic tumors are highly desmoplastic, they prevent appropriate uptake of therapeutic payloads. Thus, our objective is to develop a next-generation nanoparticle system for treating PanCa. We generated a multi-layered Pluronic F127 and polyvinyl alcohol stabilized and poly-L-lysine coated paclitaxel loaded poly(lactic-co-glycolic acid) nanoparticle formulation (PPNPs). This formulation exhibited optimal size (~160 nm) and negative Zeta potential (-6.02 mV), efficient lipid raft mediated internalization, pronounced inhibition in growth and metastasis in vitro, and in chemo-naïve and chemo-exposed orthotopic xenograft mouse models. Additionally, PPNPs altered nanomechanical properties of PanCa cells as suggested by the increased elastic modulus in nanoindentation analyses. Immunohistochemistry of orthotopic tumors demonstrated decreased expression of tumorigenic and metastasis associated proteins (ki67, vimentin and slug) in PPNPs treated mice. These results suggest that PPNPs represent a viable and robust platform for (PanCa).
Subject(s)
Nanoparticles/chemistry , Paclitaxel/therapeutic use , Pancreatic Neoplasms/drug therapy , Animals , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/drug effects , Endocytosis , Humans , Membrane Microdomains/metabolism , Mice, Nude , Neoplasm Invasiveness , Neoplasm Metastasis , Paclitaxel/pharmacology , Pancreatic Neoplasms/pathology , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Xenograft Model Antitumor AssaysABSTRACT
Pancreatic cancer is a complex disease accounting for fibrotic tumors and an aggressive phenotype. Gemcitabine (GEM) is used as a standard therapy, which develops chemoresistance leading to poor patient outcome. We have recently developed a superparamagnetic iron oxide nanoparticle (SPION) formulation of curcumin (SP-CUR), which is a nontoxic, bioactive anti-inflammatory/anti-cancer agent for its enhanced delivery in tumors. In this study, we demonstrate that SP-CUR effectively delivers bioactive curcumin to pancreatic tumors, simultaneously enhances GEM uptake and its efficacy. Mechanistic revelations suggest that SP-CUR targets tumor microenvironment via suppression of sonic hedgehog (SHH) pathway and an oncogenic CXCR4/CXCL12 signaling axis that inhibits bidirectional tumor-stromal cells interaction. Increased GEM uptake was observed due to upregulation of the human nucleoside transporter genes (DCK, hCNT) and blocking ribonucleotide reductase subunits (RRM1/RRM2). Additionally, co-treatment of SP-CUR and GEM targets cancer stem cells by regulating pluripotency maintaining stemness factors (Nanog, Sox2, c-Myc and Oct-4), and restricting tumor sphere formation. In an orthotopic mouse model, an enhanced accumulation of SP-CUR was found in pancreas, which potentiated GEM to reduce tumor growth and metastasis. Analysis of tumor tissues suggest that the treatment inhibits tumor stroma (α-SMA, Desmin and Hyluronic Acid) and induces changes in cell stiffness, as measured via Atomic Force Microscopy. This was accompanied by alteration of key cellular proteins of SHH signaling such as SHH, Gli-1, Gli-2, Sufu, and NFĸB-65 as indicated by Immunoblotting and Immunohistochemistry. These results suggest that SP-CUR has a great potential for future clinical use in the management of pancreatic cancer.