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Over the last few years, the Transforming growth factor- β (TGF-β) has been significantly considered as an effective and ubiquitous mediator of cell growth. The cytokine, TGF-β is being increasingly recognized as the most potent inducer of cancer cell initiation, differentiation, migration as well as progression through both the SMAD-dependent and independent pathways. There is growing evidence that supports the role of secretory cytokine TGF-β as a crucial mediator of tumor-stroma crosstalk. Contextually, the CAFs are the prominent component of tumor stroma that helps in tumor progression and onset of chemoresistance. The interplay between the CAFs and the tumor cells through the paracrine signals is facilitated by cytokine TGF-β to induce the malignant progression. Here in this review, we have dissected the most recent advancements in understanding the mechanisms of TGF-β induced CAF activation, their multiple origins, and most importantly their role in conferring chemoresistance. Considering the pivotal role of TGF-β in tumor perogression and associated stemness, it is one the proven clinical targets We have also included the clinical trials going on, targeting the TGF-β and CAFs crosstalk with the tumor cells. Ultimately, we have underscored some of the outstanding issues that must be deciphered with utmost importance to unravel the successful strategies of anti-cancer therapies. [ABSTRACT FROM AUTHOR]

For the identification of differentially expressed miRNAs, we employed small RNA sequencing on RNA isolated from the bone marrow (BM) of 10 subjects: five each of paediatric CN-AML patients and paediatric controls. (C) Differential expression of selected miRNAs target genes in the bone marrow of paediatric CN-AML patients (n = 32) as compared to controls (n = 15), quantified by qRT-PCR and normalised using -actin. We reported downregulation of miR-4772-5p in paediatric CN-AML patients, which is in line with an earlier study which reported low expression of serum exosomal miR-4772-3p to be a prognostic biomarker for tumour recurrence in colon cancer patients (Liu I et al i , [5]). Interestingly, while our small RNA sequencing data revealed downregulation of miR-4446-3p in paediatric CN-AML patients, it was upregulated when analysed by qRT-PCR in the larger patient population. [Extracted from the article]

Abstract: The majority of ovarian cancer patients are diagnosed in late stages of the disease, in which the tumor cells have leaked into the peritoneum and are present as tumorspheres. These tumorspheres are rich in cancer stem‐like cells (CSCs), which are resistant to therapy and are a major source of relapse. The purpose of this research was to identify a safe therapeutic approach that could eradicate the peritoneal CSC‐rich tumorspheres and inhibit relapse. Highly metastatic ascitic cells (OVASC‐1) that are resistant to standard‐of‐care chemotherapy due to upregulation of MDR1 gene were obtained from a patient with ovarian carcinoma and recurrent disease. CSC‐rich tumorspheres were generated, characterized, and treated with different chemotherapeutics. The most effective drug combination that could eradicate tumorspheres at nanomolar levels despite upregulation of MDR1 gene was identified. Luciferase‐expressing OVASC‐1 cells were implanted in the peritoneum of nude mice and treated with the identified drug combination. The progression of disease, response to therapy and recurrence were studied by quantitative imaging. Toxicity to abdominal tissues was studied by histopathology. Mice implanted with intraperitoneal (IP) OVASC‐1 xenografts showed limited response to combination therapy with cisplatin/paclitaxel at the maximum tolerated dose. Despite overexpression of MDR1 on OVASC‐1 cells, mice treated with our combination IP low‐dose MMAE and SN‐38 chemotherapy showed complete response without relapse. No signs of toxicity to abdominal tissues were observed. While MMAE and SN‐38 are not administered as free drugs due to their high potency and potential for systemic toxicity, our low‐dose localized therapy approach effectively restricted the cytotoxic effects to the tumor cells in the peritoneum. Consequently, maximum efficacy with minimal adverse effects was achieved. These remarkable results with IP low‐dose combination chemotherapy encourage investigation into its potential clinical application as either first‐line therapy or in cases of acquired resistance to cisplatin and paclitaxel. [ABSTRACT FROM AUTHOR]

The therapeutic index of poorly water-soluble drugs is often hampered due to poor pharmacokinetics, reduced blood retention, and lack of effective drug concentrations in the tumor region. In order to overcome these issues, drugs are often delivered by use of delivery vehicles to provide an enhanced therapeutic index. Gold nanoparticles synthesized in micellar networks of amphiphilic block copolymer (AuNM) provide an efficient nanocarrier for tissue- and site-specific drug delivery owing to their low cytotoxicity and immunogenicity. AuNM is formed by exploiting the properties of both inorganic Au material and an amphiphilic polymer of poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEG-PPG-PEG). We further functionalized AuNM with the FDA-approved dual tyrosine kinase inhibitor ZD6474 and studied the physicochemical properties of the conjugate ZD6474-AuNM. Both AuNM and ZD6474-AuNM, with a diameter of ~70 nm, were very stable at physiological pH. Conversely, at an acidic pH of 5.2, a slow sustained-release profile of ZD6474 was evident from AuNM, which could provide a method of facilitating release of the drug in an acidic tumor environment. In vitro, in triple-negative breast cancer cells, ZD6474-AuNM inhibited tumor cell proliferation, migration, and invasion and induced apoptosis. There was no detectable lysis of red blood cells observed when they were treated with AuNM and ZD6474-AuNM, confirming hemocompatibility. To reinforce the possibility of AuNM serving as a delivery vehicle, AuNM was conjugated with the IR680 dye for tracking, and this conjugate was systemically delivered in female nude mice bearing MDA-MB-231 human breast cancer xenografts. Fluorescence signal was retained in the tumor region in a temporal manner as compared to other organs, indicating passive retention of AuNM in the tumor locale. Moreover, delivery of ZD6474-AuNM in nude mice bearing MDA-MB-231 xenografts led to decreased tumor size as compared to the control group. The promising safety, targeting, and therapeutic results of systemic delivery of ZD6474 by AuNM provide an attractive alternative method for treating patients with metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Background: Squamous cell carcinoma of the oral cavity (SCCOC) is the dominant origin of cancer associated mortality. Previous findings by our study reported that acquisition of anoikis resistance has a significant role in tumor progression of oral cavity. Several genes were over-expressed in anoikis-resistant cells under detached conditions which we confirmed earlier by microarray. Normal oral squamous epithelia grow adherent to a basement membrane, and when detached from the extracellular matrix, undergoes programmed cell death. The acquisition of anoikis-resistance is crucial phenomena in oral tumor advancement. In the current study, we have identified S100A7 expression as contributing factor for anoikis resistance and tumorigenicity in human oral cancer cells. Further, we have explored that elevated S100A7 expression in anoikis-sensitive oral keratinocytes and cancer cells reshape them more resistant to anoikis and apoptosis inducers via activation of cellular intrinsic and extrinsic avenue. Methods: A subset of human cancer cell lines TU167, JMAR, JMARC39, JMARC42 and MDA-MB-468 were utilized for the generation of resistant stable cell lines. Further, immunohistochemistry, western blot and immunoprecipitation, assays of apoptosis, soft agar assay, orthotopic animal model and signaling elucidation were performed to establish our hypothesis. Results: S100A7 gene is found to be responsible for anoikis resistance and tumorigenicity in human oral cancer cells. We have observed up-regulation of S100A7 in anoikis resistant cell lines, orthotropic model and patients samples with head and neck cancer. It is also noticed that secretion of S100A7 protein in conditioned medium by anoikis resistant head & neck cancer cell and in saliva of head and neck cancer patients. Up-regulation of S100A7 expression has triggered enhanced tumorigenicity and anchorage-independent growth of cancer cells through Akt phosphorylation leading to development of aniokis resistance in head and neck cancer cells. Conclusions: These data have led us to conclude that S100A7 is the major contributing factor in mediating anoikisresistance of oral cancer cells and local tumor progression, and S100A7 might be useful as diagnostic marker for early detection of primary and recurrent squamous cell cancer. [ABSTRACT FROM AUTHOR]

Single drug therapies for cancer are often suboptimal and may not provide long term clinical benefits. To overcome this obstacle for effective treatment the applications of two or more drugs are preferable. A limitation of multidrug use is the varying pharmacokinetics of different drugs. To overcome these impediments, we designed and synthesized multi-layered polyvinyl alcohol tethered hollow manganese ferrite nanocarriers capable of encapsulating two drugs with unique attributes of sensitivity towards tumor acidic milieu, mono-dispersive, compactness and high encapsulation efficiency. We encapsulated tamoxifen and diosgenin in the peripheral and subsequent inner layers of multilayered nanocarriers. In vitro and in vivo studies evaluated the nanocarrier uptake and retention ability of the tumor through magnetic saturation studies and elucidated the molecular mechanisms mediating drug(s)-induced apoptosis. The acidity of the tumor environment triggers extracellular dissociation of the peripheral coats resulting in release of tamoxifen blocking the estrogen receptor. The partially degraded nanocarriers localize intracellularly through endosomal escape and release diosgenin. Nanocarrier treatment reduced the cellular levels of Bcl2 and p53, while increasing the levels of Bim. This delivery system successfully embodies the sequential release of drugs and may provide a therapeutic strategy for sequentially affecting multiple targets in advanced cancers. [ABSTRACT FROM AUTHOR]

Background The hypoxic environment of tumor region stimulated the up regulation of growth factors responsible for angiogenesis and tumor proliferation. Thus, targeting the tumor vasculature along with the proliferation by dual tyrosine kinase inhibitor may be the efficient way of treating advanced breast cancers, which can be further enhanced by combining with radiotherapy. However, the effectiveness of radiotherapy may be severely compromised by toxicities and tumor resistance due to radiation-induced adaptive response contributing to recurrence and metastases of breast cancer. The rational of using ZD6474 is to evaluate the feasibility and efficacy of combined VEGFR2 and EGFR targeting with concurrent targeted and localized UV-B phototherapy in vitro breast cancer cells with the anticipation to cure skin lesions infiltrated with breast cancer cells. Materials and methods Breast cancer cells were exposed to UV-B and ZD6474 and the cell viability, apoptosis, invasion and motility studies were conducted for the combinatorial effect. Graphs and statistical analyses were performed using Graph Pad Prism 5.0. Results ZD6474 and UV-B decreased cell viability in breast cancers in combinatorial manner without affecting the normal human mammary epithelial cells. ZD6474 inhibited cyclin E expression and induced p53 expression when combined with UV-B. It activated stress induced mitochondrial pathway by inducing translocation of bax and cytochrome-c. The combination of ZD6474 with UV-B vs. either agent alone also more potently down-regulated the antiapoptotic bcl-2 protein, up-regulated pro-apoptotic signaling events involving expression of bax, activation of caspase-3 and caspase-7 proteins, and induced poly (ADP-ribose) polymerase resulting in apoptosis. ZD6474 combined with UV-B inhibited invasion of breast cancer cells in vitro as compared to either single agent, indicating a potential involvement of pro-angiogenic growth factors in regulating the altered expression and reorganization of cytoskeletal proteins in combinatorial treated breast cancer cells. Involvement of combination therapy in reducing the expression of matrix metalloprotease was also observed. Conclusions Collectively, our studies indicate that incorporating an anti-EGFR plus VEGFR strategy (ZD6474) with phototherapy (UV-B), an alternative approach to the ongoing conventional radiotherapy for the treatment of infiltrating metastatic breast cancer cells in the skin and for locally recurrence breast cancer than either approach alone. [ABSTRACT FROM AUTHOR]

X-linked inhibitor of apoptosis protein (XIAP) is constitutively expressed endogenous inhibitor of apoptosis, exhibit its antiapoptotic effect by inactivating key caspases such as caspase-3, caspase-7 and caspase-9 and also play pivotal role in rendering cancer chemoresistance. Our studies showed the coadministration of TQ and TAM resulting in a substantial increase in breast cancer cell apoptosis and marked inhibition of cell growth both in vitro and in vivo. Anti-angiogenic and anti-invasive potential of TQ and TAM was assessed through in vitro studies. This novel combinatorial regimen leads to regulation of multiple cell signaling targets including inactivation of Akt and XIAP degradation. At molecular level, TQ and TAM synergistically lowers XIAP expression resulting in binding and activation of caspase-9 in apoptotic cascade, and interfere with cell survival through PI3-K/Akt pathway by inhibiting Akt phosphorylation. Cleaved caspase-9 further processes other intracellular death substrates such as PARP thereby shifting the balance from survival to apoptosis, indicated by rise in the sub-G1 cell population. This combination also downregulates the expression of Akt-regulated downstream effectors such as Bcl-xL, Bcl-2 and induce expression of Bax, AIF, cytochrome C and p-27. Consistent with these results, overexpression studies further confirmed the involvement of XIAP and its regulatory action on Akt phosphorylation along with procaspase-9 and PARP cleavage in TQ-TAM coadministrated induced apoptosis. The ability of TQ and TAM in inhibiting XIAP was confirmed through siRNA-XIAP cotransfection studies. This novel modality may be a promising tool in breast cancer treatment. [ABSTRACT FROM AUTHOR]

Adenovirus (Ad)-based gene therapy represents a potentially viable strategy for treating colorectal cancer. The infectivity of serotype 5 adenovirus (Ad.5), routinely used as a transgene delivery vector, is dependent on Coxsackie-adenovirus receptors (CAR). CAR expression is downregulated in many cancers thus preventing optimum therapeutic efficiency of Ad.5-based therapies. To overcome the low CAR problem, a serotype chimerism approach was used to generate a recombinant Ad (Ad.5/3) that is capable of infecting cancer cells via Ad.3 receptors in a CAR-independent manner. We evaluated the improved transgene delivery and efficacy of Ad.5/3 recombinant virus expressing melanoma differentiation associated gene-7/interleukin-24 ( mda-7/IL-24), an effective wide-spectrum cancer-selective therapeutic. In low CAR human colorectal cancer cells RKO, wild-type Ad.5 virus expressing mda-7/IL-24 (Ad.5- mda-7) failed to infect efficiently resulting in lack of expression of MDA-7/IL-24 or induction of apoptosis. However, a recombinant Ad.5/3 virus expressing mda-7/IL-24 (Ad.5/3- mda-7) efficiently infected RKO cells resulting in higher MDA-7/IL-24 expression and inhibition of cell growth both in vitro and in nude mice xenograft models. Addition of the novel Bcl-2 family pharmacological inhibitor Apogossypol derivative BI-97C1 (Sabutoclax) significantly augmented the efficacy of Ad.5/3- mda-7. A combination regimen of suboptimal doses of Ad.5/3- mda-7 and BI-97C1 profoundly enhanced cytotoxicity in RKO cells both in vitro and in vivo. Considering the fact that Ad.5- mda-7 has demonstrated significant objective responses in a Phase I clinical trial for advanced solid tumors, Ad.5/3- mda-7 alone or in combination with BI-97C1 would be predicted to exert significantly improved therapeutic efficacy in colorectal cancer patients. J. Cell. Physiol. 227: 2145-2153, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Immunohistochemical markers have been proposed for thyroid cancer diagnosis and prognostic studies. Immunohistochemical analysis of CK-19, NF-κB, β-catenin, E-cadherin and EGFR were done to evaluate their diagnostic and prognostic efficiencies in eighty eight cancer specimen (PTC-52, FTC-16, benign nodule-12 and MNG-8). CK-19 was positive in 91% (62/68) DTC, 98% (51/52) PTC, 69% (11/16) FTC and 15% (3/20) benign thyroid nodules. NF-κB was expressed 93% (63/68) DTC, in 96% (50/52) PTC, 81% (11/16) FTC and 15% (3/20) benign thyroid nodules. Both CK-19 and NF-κB were significantly differentiated DTC, PTC and FTC from benign thyroid nodule (p

Chemotherapy employing paclitaxel and docetaxel is widely used for treating early-stage breast cancer and metastasis, which is frequently associated with overexpression of epidermal growth factor receptor (EGFR) and resistance to apoptosis. ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR, inhibits cell proliferation of solid tumors, including breast. Phase III clinical trials using ZD6474 in non-small cell lung carcinoma when combined with standard chemotherapy appear promising. In order to improve the antineoplastic activity of paclitaxel, we presently investigated the effects of ZD6474 in combination with paclitaxel in EGFR and VEGFR expressing human breast cancer cell lines MCF-7 and MDA-MB-231. ZD6474 synergistically decreased cell viability when used in combination with paclitaxel. ZD6474 inhibited cyclin D1 and cyclin E expression and induced p53 expression when combined with paclitaxel. The combination of ZD6474 with paclitaxel versus either agent alone also more potently down-regulated the antiapoptotic bcl-2 protein, up-regulated pro-apoptotic signaling events involving expression of bax, activation of caspase-3 and caspase-7 proteins, and induced poly(ADP-ribose) polymerase resulting in apoptosis. ZD6474 combined with paclitaxel inhibited anchorage-independent colony formation and invasion of breast cancer cells in vitro as compared to either single agent, indicating a potential involvement of altered expression and reorganization of cytoskeletal proteins in combinatorial treated breast cancer cells. Collectively, our studies indicate that incorporating an anti-EGFR plus VEGFR strategy (ZD6474) with chemotherapy (paclitaxel), where clinical studies of dose-intensive paclitaxel therapy are currently in progress, may be more effective in treating patients with locally advanced or metastatic breast cancer than either approach alone. J. Cell. Physiol. 226: 375-384, 2011. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Thyroid tumor contributes 1% of the total tumor but 90% of the endocrine related tumors. Majority of the thyroid cancers are being diagnosed by Fine needle aspiration cytology (FNAC) and histology. Although histology is considered as gold standard, it has some limitations, like variants of papillary and follicular cancer creates confusion among pathologists, where the morphological features are indistinguishable. Conventional histology and FNAC fails to provide any prognostic and therapeutic information. To address this problem, several immunohistochemical markers are proposed and their efficiency in thyroid cancer diagnosis, treatment and prognosis are being evaluated. Among the discussed immunohistochemical markers, few have potential in accurate diagnosis and prognosis of thyroid carcinoma. Hector battifora mesothelial antigen-1 (HBME-1) and Galectin-3 (GAL-3) shows highest speci- ficity and sensitivity in the diagnosis of thyroid cancer respectively. Overexpression of EGFR in thyroid cancer is in proportionate with the severity of the advanced thyroid carcinoma, which required further evaluation and validation. Surgery and radio-iodine therapy is the main treatment modality, however; combined targeted therapeutic approach against different thyroid cancer receptor and biomarkers can reduce the side effect, and improve therapeutic efficiency. This review is oriented towards the finding of the potent thyroid cancer receptor having enhanced sensitivity and specificity, with diagnostic, prognostic and therapeutic efficiency. [ABSTRACT FROM AUTHOR]

Biomarkers of breast cancer are necessary for prognosis and prediction to chemotherapy. Prognostic biomarkers provide information regarding outcome irrespective of therapy, while predictive biomarkers provide information regarding response to therapy. Candidate prognostic biomarkers for breast cancers are growth factor receptors, steroid receptors, Ki-67, cyclins, urokinase plasminogen activator, p53, p21, pro- and anti-apoptotic factors, BRCA1 and BRCA2. But currently, the predictive markers are Estrogen and Progesterone receptors responding to endocrine therapy, and HER-2 responding to herceptin. But there are numerous breast cancer cases, where tamoxifen is ineffective even after estrogen receptor positivity. This lead to search of new prognostic and predictive markers and the number of potential markers is constantly increasing due to proteomics and genomics studies. However, most biomarkers individually have poor sensitivity or specificity, or other clinical value. It can be resolved by studying various biomarkers simultaneously, which will help in better prognosis and increasing sensitivity for chemotherapeutic agents. This review is focusing on growth factor receptors, apoptosis markers, signaling cascades, and their correlation with other associated biomarkers in breast cancers. As our knowledge regarding molecular biomarkers for breast cancer increases, prognostic indices will be developed that combine the predictive power of individual molecular biomarkers with specific clinical and pathologic factors. Rigorous comparison of these existing as well as emerging markers with current treatment selection is likely to see an escalation in an era of personalized medicines to ensure the breast cancer patients receive optimal treatment. This will also solve the treatment modalities and complications related to chemotherapeutic regimens. [ABSTRACT FROM AUTHOR]

An aptamer is a short sequence of synthetic oligonucleotides which bind to their cognate target, specifically while maintaining similar or higher sensitivity compared to an antibody. The in-vitro selection of an aptamer, applying a conjoining approach of chemistry and molecular biology, is referred as Systematic Evolution of Ligands by Exponential enrichment (SELEX). These initial products of SELEX are further modified chemically in an attempt to make them stable in biofluid, avoiding nuclease digestion and renal clearance. While the modification is incorporated, enough care should be taken to maintain its sensitivity and specificity. These modifications and several improvisations have widened the window frame of aptamer applications that are currently not only restricted to in-vitro systems, but have also been used in molecular imaging for disease pathology and treatment. In the food industry, it has been used as sensor for detection of different diseases and fungal infections. In this review, we have discussed a brief history of its journey, along with applications where its role as a therapeutic plus diagnostic (theranostic) tool has been demonstrated. We have also highlighted the potential aptamer-mediated strategies for molecular targeting of COVID-19. Finally, the review focused on its future prospective in immunotherapy, as well as in identification of novel biomarkers in stem cells and also in single cell proteomics (scProteomics) to study intra or inter-tumor heterogeneity at the protein level. Small size, chemical synthesis, low batch variation, cost effectiveness, long shelf life and low immunogenicity provide advantages to the aptamer over the antibody. These physical and chemical properties of aptamers render them as a strong biomedical tool for theranostic purposes over the existing ones. The significance of aptamers in human health was the key finding of this review. [ABSTRACT FROM AUTHOR]

Cancer-selective viral replication and delivery of a therapeutic immunomodulating, cancer-selective killing cytokine (mda-7/IL-24) by means of a newCancer Terminator Virus(CTV) combined with a small molecule BH3 mimetic holds promise for treating both primary and metastatic hormone refractory prostate cancer (CaP). [ABSTRACT FROM PUBLISHER]

Low pH in the tumor micromilieu is a recognized pathological feature of cancer. This attribute of cancerous cells has been targeted herein for the controlled release of chemotherapeutics at the tumour site, while sparing healthy tissues. To this end, pH-sensitive, hollow ZnO-nanocarriers loaded with paclitaxel were synthesized and their efficacy studied in breast cancer in vitro and in vivo. The nanocarriers were surface functionalized with folate using click-chemistry to improve targeted uptake by the malignant cells that over-express folate-receptors. The nanocarriers released ~75% of the paclitaxel payload within six hours in acidic pH, which was accompanied by switching of fluorescence from blue to green and a 10-fold increase in the fluorescence intensity. The fluorescence-switching phenomenon is due to structural collapse of the nanocarriers in the endolysosome. Energy dispersion X-ray mapping and whole animal fluorescent imaging studies were carried out to show that combined pH and folate-receptor targeting reduces off-target accumulation of the nanocarriers. Further, a dual cell-specific and pH-sensitive nanocarrier greatly improved the efficacy of paclitaxel to regress subcutaneous tumors in vivo. These nanocarriers could improve chemotherapy tolerance and increase anti-tumor efficacy, while also providing a novel diagnostic read-out through fluorescent switching that is proportional to drug release in malignant tissues. [ABSTRACT FROM AUTHOR]

Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small-molecule BH3 mimetic, inhibits the function of antiapoptotic Bcl-2 proteins. Minocycline, a synthetic tetracycline, displays antitumor activity. Here, we offer evidence of the combinatorial antitumor potency of these agents in several preclinical models of pancreatic cancer. Sabutoclax induced growth arrest and apoptosis in pancreatic cancer cells and synergized with minocycline to yield a robust mitochondria-mediated caspase-dependent cytotoxicity. This combinatorial property relied upon loss of phosphorylated Stat3 insofar as reintroduction of activated Stat3-rescued cells from toxicity. Tumor growth was inhibited potently in both immune-deficient and immune-competent models with evidence of extended survival. Overall, our results showed that the combination of sabutoclax and minocycline was highly cytotoxic to pancreatic cancer cells and safely efficacious in vivo. [ABSTRACT FROM AUTHOR]

We describe a new imaging method for detecting prostate cancer, whether localized or disseminated and metastatic to soft tissues and bone. The method relies on the use of imaging reporter genes under the control of the promoter of AEG-1 (MTDH), which is selectively active only in malignant cells. Through a systemic, nanoparticle-based delivery of the imaging construct, lesions can be identified through bioluminescence imaging and single-photon emission computed tomography in the PC3-ML murine model of prostate cancer at high sensitivity. This approach is applicable for the detection of prostate cancer metastases, including bone lesions for which there is no current reliable agent for noninvasive clinical imaging. Furthermore, the approach compares favorably with accepted and emerging clinical standards, including PET with [18F]fluorodeoxyglucose and [18F]sodium fluoride. Our results offer a preclinical proof of concept that rationalizes clinical evaluation in patients with advanced prostate cancer. [ABSTRACT FROM AUTHOR]

Subtraction hybridization combined with induction of cancer cell terminal differentiation in human melanoma cells identified melanoma differentiation--associated gene-7/interleukin-24 (mda-7/IL-24) and SARI (suppressor of AP-1, induced by IFN) that display potent antitumor activity. These genes are not constitutively expressed in cancer cells and forced expression of mda-7/IL-24 (Ad.mda-7) or SARI (Ad.SARI) promotes cancer-specific cell death. Ectopic expression of mda-7/IL-24 induces SARI mRNA and protein in a panel of different cancer cells, leading to cell death, without harming corresponding normal cells. Simultaneous inhibition of K-ras downstream extracellular signal-regulated kinase 1/2 signaling in pancreatic cancer cells reverses the translational block of MDA-7/IL-24 and induces SARI expression and cell death. Using SARI-antisense-based approaches, we demonstrate that SARI expression is necessary for mda-7/IL-24 antitumor effects. Secreted MDA-7/IL-24 protein induces antitumor "bystander" effects by promoting its own expression. Recombinant MDA-7/IL-24 (His-MDA-7) induces SARI expression, supporting the involvement of SARI in the MDA-7/IL-24-driven autocrine loop, culminating in antitumor effects. Moreover, His-MDA-7, after binding to its cognate receptors (IL-20R1/IL-20R2 or IL-22R/IL- 20R2), induces intracellular signaling by phosphorylation of p38 MAPK, leading to transcription of a family of growth arrest and DNA damage inducible (GADD) genes, culminating in apoptosis. Inhibition of p38 MAPK fails to induce SARI following Ad.mda-7 infection. These findings reveal the significance of the mda-7/IL-24-SARI axis in cancer-specific killing and provide a potential strategy for treating both local and metastatic disease. [ABSTRACT FROM AUTHOR]

Purpose: The emergence of highly mutated and transmissible BA variants has caused an unprecedented surge in COVID-19 infections worldwide. Thorough analysis of its genome structure and phylogenomic evolutionary details will serve as scientific reference for future research., Method: Here, we have analyzed the BA variants from India using whole-genome sequencing, spike protein mutation study, spatio-temporal surveillance, phylogenomic assessment and epitope mapping., Results: The predominance of BA.2/BA.2-like was observed in India during COVID-19 third wave. Genome analysis and mutation study highlighted the existence of 2128 amino acid changes within BA as compared to NC_045512.2. Presence of 23 unknown mutation sites (spanning region 61-831) were observed among the Indian BA variants as compared to the global BA strains. Unassigned probable Omicron showed the highest number of mutations (370) followed by BA.1 (104), BA.2.3 (56), and BA.2 (27). Presence of mutations 'Q493R ​+ ​Q498R ​+ ​N501Y', and 'K417 ​N ​+ ​E484A ​+ ​N501Y' remained exclusive to BA.2 as well as unassigned probable Omicron. The time-tree and phylogenomic network assessed the evolutionary relationship of the BA variants. Existence of 424 segregating sites and 113 parsimony informative sites within BA genomes were observed through haplotype network analysis. Epitope mapping depicted the presence of unique antigenic sites within the receptor binding domain of the BA variants that could be exploited for robust vaccine development., Conclusion: These findings provide important scientific insights about the nature, diversity, and evolution of Indian BA variants. The study further divulges in the avenues of therapeutic upgradation for better management and eventual eradication of COVID-19., Competing Interests: Declaration of competing interest All the authors declare that no competing interests exist., (Copyright © 2022 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Tamoxifen administration enhanced overall disease-free survival and diminished mortality rates in cancer patients. However, patients with breast cancer often fail to respond for tamoxifen therapy due to the development of a drug-resistant phenotype. Functional analysis and molecular studies suggest that protein mutation and dysregulation of survival signaling molecules such as epidermal growth factor receptor, vascular endothelial growth factor receptor 2, and Akt contribute to tamoxifen resistance. Various strategies, including combinatorial therapies, show chemosensitize tamoxifen-resistant cancers. Based on chemotoxicity issues, researchers are actively investigating alternative therapeutic strategies. In the current study, we fabricate a mesoporous silica gold cluster nanodrug delivery system that displays exceptional tumor-targeting capability, thus promoting accretion of drug indices at the tumor site. We employ dual drugs, ZD6474, and epigallocatechin gallate (EGCG) that inhibit EGFR2, VEGFR2, and Akt signaling pathways since changes in these signaling pathways confer tamoxifen resistance in MCF 7 and T-47D cells. Mesoporous silica gold cluster nanodrug delivery of ZD6474 and EGCG sensitize tamoxifen-resistant cells to apoptosis. Western and immune-histochemical analyses confirmed the apoptotic inducing properties of the nanoformulation. Overall, results with these silica gold nanoclusters suggest that they may be a potent nanoformulation against chemoresistant cancers.

Akt overexpression in cancer causes resistance to traditional chemotherapeutics. Silencing Akt through siRNA provides new therapeutic options; however, poor in vivo siRNA pharmacokinetics impede translation. We demonstrate that acidic milieu-sensitive multilamellar gold niosomes (Nio-Au) permit targeted delivery of both Akt-siRNA and thymoquinone (TQ) in tamoxifen-resistant and Akt-overexpressing MCF7 breast cancer cells. Octadecylamine groups of functionalized gold nanoparticles impart cationic attribute to niosomes, stabilized through polyethylene glycol. TQ's aqueous insolubility renders its encapsulation within hydrophobic core, and negatively charged siRNA binds in hydrophilic region of cationic niosomes. These niosomes were exploited to effectively knockdown Akt, thereby sensitizing cells to TQ. Immunoblot studies revealed enhanced apoptosis by inducing p53 and inhibiting MDM2 expression, which was consistent with in vivo xenograft studies. This innovative strategy, using Nio-Au to simultaneously deliver siRNA (devoid of any chemical modification) and therapeutic drug, provides an efficacious approach for treating therapy-resistant cancers with significant translational potential.

Cancer-selective viral replication and delivery of a therapeutic immunomodulating, cancer-selective killing cytokine ( mda-7/IL-24 ) by means of a new Cancer Terminator Virus ( CTV ) combined with a small molecule BH3 mimetic holds promise for treating both primary and metastatic hormone refractory prostate cancer (CaP).

Despite recent advances, treatment options for advanced prostate cancer (CaP) remain limited. We are pioneering approaches to treat advanced CaP that employ conditionally replication-competent oncolytic adenoviruses that simultaneously produce a systemically active cancer-specific therapeutic cytokine, mda-7/IL-24, Cancer Terminator Viruses (CTV). A truncated version of the CCN1/CYR61 gene promoter, tCCN1-Prom, was more active than progression elevated gene-3 promoter (PEG-Prom) in regulating transformation-selective transgene expression in CaP and oncogene-transformed rat embryo cells. Accordingly, we developed a new CTV, Ad.tCCN1-CTV-m7, which displayed dose-dependent killing of CaP without harming normal prostate epithelial cells in vitro with significant anti-cancer activity in vivo in both nude mouse CaP xenograft and transgenic Hi-Myc mice (using ultrasound-targeted microbubble (MB)-destruction, UTMD, with decorated MBs). Resistance to mda-7/IL-24-induced cell death correlated with overexpression of Bcl-2 family proteins. Inhibiting Mcl-1 using an enhanced BH3 mimetic, BI-97D6, sensitized CaP cell lines to mda-7/IL-24-induced apoptosis. Combining BI-97D6 with Ads expressing mda-7/IL-24 promoted ER stress, decreased anti-apoptotic Mcl-1 expression and enhanced mda-7/IL-24 expression through mRNA stabilization selectively in CaP cells. In Hi-myc mice, the combination induced enhanced apoptosis and tumor growth suppression. These studies highlight therapeutic efficacy of combining a BH3 mimetic with a novel CTV, supporting potential clinical applications for treating advanced CaP.

Pancreatic cancer is an aggressive disease with limited therapeutic options. Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), a potent antitumor cytokine, shows cancer-specific toxicity in a vast array of human cancers, inducing endoplasmic reticulum stress and apoptosis, toxic autophagy, an antitumor immune response, an antiangiogenic effect, and a significant "bystander" anticancer effect that leads to enhanced production of this cytokine through autocrine and paracrine loops. Unfortunately, mda-7/IL-24 application in pancreatic cancer has been restricted because of a "translational block" occurring after Ad.5-mda-7 gene delivery. Our previous research focused on developing approaches to overcome this block and increase the translation of the MDA-7/IL-24 protein, thereby promoting its subsequent toxic effects in pancreatic cancer cells. We demonstrated that inducing reactive oxygen species (ROS) after adenoviral infection of mda-7/IL-24 leads to greater translation into MDA-7/IL-24 protein and results in toxicity in pancreatic cancer cells. In this study we demonstrate that a novel chimeric serotype adenovirus, Ad.5/3-mda-7, displays greater efficacy in delivering mda-7/IL-24 compared with Ad.5-mda-7, although overall translation of the protein still remains low. We additionally show that d-limonene, a dietary monoterpene known to induce ROS, is capable of overcoming the translational block when used in combination with adenoviral gene delivery. This novel combination results in increased polysome association of mda-7/IL-24 mRNA, activation of the preinitiation complex of the translational machinery in pancreatic cancer cells, and culminates in mda-7/IL-24-mediated toxicity., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Few options are available for treating patients with advanced prostate cancer (PC). As PC is a slow growing disease and accessible by ultrasound, gene therapy could provide a viable option for this neoplasm. Conditionally replication-competent adenoviruses (CRCAs) represent potentially useful reagents for treating PC. We previously constructed a CRCA, cancer terminator virus (CTV), which showed efficacy both in vitro and in vivo for PC. The CTV was generated on a serotype 5-background (Ad.5-CTV) with infectivity depending on Coxsackie-Adenovirus Receptors (CARs). CARs are frequently reduced in many tumor types, including PCs thereby limiting effective Ad-mediated therapy. Using serotype chimerism, a novel CTV (Ad.5/3-CTV) was created by replacing the Ad.5 fiber knob with the Ad.3 fiber knob thereby facilitating infection in a CAR-independent manner. We evaluated Ad.5/3-CTV in comparison with Ad.5-CTV in low CAR human PC cells, demonstrating higher efficiency in inhibiting cell viability in vitro. Moreover, Ad.5/3-CTV potently suppressed in vivo tumor growth in a nude mouse xenograft model and in a spontaneously induced PC that develops in Hi-myc transgenic mice. Considering the significant responses in a Phase I clinical trial of a non-replicating Ad.5-mda-7 in advanced cancers, Ad.5/3-CTV may exert improved therapeutic benefit in a clinical setting., (© 2013 Wiley Periodicals, Inc.)

Structure-based modeling combined with rational drug design, and high throughput screening approaches offer significant potential for identifying and developing lead compounds with therapeutic potential. The present review focuses on these two approaches using explicit examples based on specific derivatives of Gossypol generated through rational design and applications of a cancer-specificpromoter derived from Progression Elevated Gene-3. The Gossypol derivative Sabutoclax (BI-97C1) displays potent anti-tumor activity against a diverse spectrum of human tumors. The model of the docked structure of Gossypol bound to Bcl-XL provided a virtual structure-activity-relationship where appropriate modifications were predicted on a rational basis. These structure-based studies led to the isolation of Sabutoclax, an optically pure isomer of Apogossypol displaying superior efficacy and reduced toxicity. These studies illustrate the power of combining structure-based modeling with rational design to predict appropriate derivatives of lead compounds to be empirically tested and evaluated for bioactivity. Another approach to cancer drug discovery utilizes a cancer-specific promoter as readouts of the transformed state. The promoter region of Progression Elevated Gene-3 is such a promoter with cancer-specific activity. The specificity of this promoter has been exploited as a means of constructing cancer terminator viruses that selectively kill cancer cells and as a systemic imaging modality that specifically visualizes in vivo cancer growth with no background from normal tissues. Screening of small molecule inhibitors that suppress the Progression Elevated Gene-3-promoter may provide relevant lead compounds for cancer therapy that can be combined with further structure-based approaches leading to the development of novel compounds for cancer therapy.

No single or combinatorial therapeutic approach has proven effective in decreasing morbidity or engendering a cure of metastatic cancer. In principle, conditionally replication-competent adenoviruses that induce tumor oncolysis through cancer-specific replication hold promise for cancer therapy. However, a single-agent approach may not be adequate to completely eradicate cancer in a patient because most cancers arise from abnormalities in multiple genetic and signal transduction pathways and targeting disseminated metastases is difficult to achieve. Based on these considerations, a novel class of cancer destroying adenoviruses have been produced, cancer terminator viruses (CTVs), in which cancer-specific replication is controlled by the progression-elevated gene-3 promoter and replicating viruses produce a second transgene encoding an apoptosis-inducing and immunomodulatory cytokine, either melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) or interferon-γ. This review focuses on these viruses and ways to improve their delivery systemically and enhance their therapeutic efficacy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: Human cancers are genetically and epigenetically heterogeneous and have the capacity to commandeer a variety of cellular processes to aid in their survival, growth and resistance to therapy. One strategy is to overexpress proteins that suppress apoptosis, such as the Bcl-2 family protein Mcl-1. The Mcl-1 protein plays a pivotal role in protecting cells from apoptosis and is overexpressed in a variety of human cancers., Areas Covered: Targeting Mcl-1 for extinction in these cancers, using genetic and pharmacological approaches, represents a potentially effectual means of developing new efficacious cancer therapeutics. Here we review the multiple strategies that have been employed in targeting this fundamental protein, as well as the significant potential these targeting agents provide in not only suppressing cancer growth, but also in reversing resistance to conventional cancer treatments., Expert Opinion: We discuss the potential issues that arise in targeting Mcl-1 and other Bcl-2 anti-apoptotic proteins, as well problems with acquired resistance. The application of combinatorial approaches that involve inhibiting Mcl-1 and manipulation of additional signaling pathways to enhance therapeutic outcomes is also highlighted. The ability to specifically inhibit key genetic/epigenetic elements and biochemical pathways that maintain the tumor state represent a viable approach for developing rationally based, effective cancer therapies.

Prostate cancer is the second leading cause of cancer-related deaths in men in the U.S. At present, no single or combination therapy has shown efficacy in decreasing disease progression in patients with metastatic disease. A potentially viable approach for treating late-stage prostate cancer is gene therapy. Adenoviruses (Ad) are the most commonly used mode of gene delivery, but progress using this vector has been hampered by concerns over the safety and practicality of viruses including conditionally replicating Ads (CRAds), particularly for intravenous delivery, and the inefficiency of non-viral transfection techniques. Major challenges for effective gene therapy using Ads are the limited infectivity of regular Ad serotype 5 (Ad5) and the inability to specifically deliver the therapeutic directly into diseased tissue without trapping in the liver or elimination by the immune system. The shortcoming in using Ad5 is mostly attributed to a reduction in Coxsackie-adenovirus receptors (CAR) on the surface of cancer cells, which can be mitigated by generating tropism-modified Ads permitting CAR-independent infection of tumor cells. The limitations of systemic gene delivery can now be overcome by using a novel targeted-delivery approach such as ultrasound (US) contrast agents (microbubbles) to deliver effective therapeutic reagents, Ads, or recombinant proteins, combined with ultrasound-targeted microbubble destruction (UTMD), to develop a site-specific therapy in immune competent transgenic mouse models. These unique strategies for enhancing the efficacy of gene therapy provide a direct path to translation from the laboratory into the clinic for developing an effective gene therapy of prostate cancer.