Deciphering cellular and molecular mechanism of MUC13 mucin involved in cancer cell plasticity and drug resistance.

There has been a surge of interest in recent years in understanding the intricate mechanisms underlying cancer progression and treatment resistance. One molecule that has recently emerged in these mechanisms is MUC13 mucin, a transmembrane glycoprotein. Researchers have begun to unravel the molecular complexity of MUC13 and its impact on cancer biology. Studies have shown that MUC13 overexpression can disrupt normal cellular polarity, leading to the acquisition of malignant traits. Furthermore, MUC13 has been associated with increased cancer plasticity, allowing cells to undergo epithelial-mesenchymal transition (EMT) and metastasize. Notably, MUC13 has also been implicated in the development of chemoresistance, rendering cancer cells less responsive to traditional treatment options. Understanding the precise role of MUC13 in cellular plasticity, and chemoresistance could pave the way for the development of targeted therapies to combat cancer progression and enhance treatment efficacy.

Clinical Implications of Exosomes: Targeted Drug Delivery for Cancer Treatment.

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.

Protein kinase D1 regulates metabolic switch in pancreatic cancer via modulation of mTORC1.

BACKGROUND: Protein kinase D1 (PKD1) is a serine-threonine kinase that regulates various functions within the cell. Herein, we report the significance of PKD1 expression in glucose metabolism resulting in pancreatic cancer (PanCa) progression and chemo-resistance. METHODS: PKD1 expression in PanCa was investigated by using immunohistochemistry. Functional and metabolic assays were utilised to analyse the effect of PKD1 expression/knockdown on associated cellular/molecular changes. RESULTS: PKD1 expression was detected in human pancreatic intraepithelial neoplasia lesions (MCS = 12.9; P < 0.0001) and pancreatic ductal adenocarcinoma samples (MCS = 15, P < 0.0001) as compared with faint or no expression in normal pancreatic tissues (MCS = 1.54; P < 0.0001). Our results determine that PKD1 enhances glucose metabolism in PanCa cells, by triggering enhanced tumorigenesis and chemo-resistance. We demonstrate that mTORC1 activation by PKD1 regulates metabolic alterations in PanCa cells. siRNA knockdown of Raptor or treatment with rapamycin inhibited PKD1-accelerated lactate production as well as glucose consumption in cells, which confirms the association of mTORC1 with PKD1-induced metabolic alterations. CONCLUSION: This study suggests a novel role of PKD1 as a key modulator of the glucose metabolism in PanCa cells accelerating tumorigenesis and chemo-resistance. The remodelling of PKD1-dysregulated glucose metabolism can be achieved by regulation of mTORC1 for development of novel therapeutic strategies.

APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF.

Pancreatic cancer is the worst exocrine gastrointestinal cancer leading to the highest mortality. Recent studies reported that aberrant expression of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is involved in uncontrolled cell growth. However, the molecular mechanism of APE1 biological role remains unrevealed in pancreatic cancer progression. Here, we demonstrate that APE1 accelerates pancreatic cancer cell proliferation through glial cell line-derived neurotrophic factor (GDNF)/glial factor receptor α1 (GFRα1)/Src/ERK axis-cascade signaling. The proliferation of endogenous APE1 expressed-MIA PaCa-2, a human pancreatic carcinoma cell line, was increased by treatment with GDNF, a ligand of GFRα1. Either of downregulated APE1 or GFRα1 expression using small interference RNA (siRNA) inhibited GDNF-induced cancer cell proliferation. The MEK-1 inhibitor PD98059 decreased GDNF-induced MIA PaCa-2 cell proliferation. Src inactivation by either its siRNA or Src inhibitor decreased ERK-phosphorylation in response to GDNF in MIA PaCa-2 cells. Overexpression of GFRα1 in APE1-deficient MIA PaCa-2 cells activated the phosphorylation of Src and ERK. The expression of both APE1 and GFRα1 was gradually increased as progressing pancreatic cancer grades. Our results highlight a critical role for APE1 in GDNF-induced pancreatic cancer cell proliferation through APE1/GFRα1/Src/ERK axis-cascade signaling and provide evidence for future potential therapeutic drug targets for the treatment of pancreatic cancer.

Next-generation paclitaxel-nanoparticle formulation for pancreatic cancer treatment.

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).

Frequency of mirror movements and comparison of hand function in spastic cerebral palsy children with and without mirror movements.

OBJECTIVE: To assess the frequency of mirror movements in spastic cerebral palsy children and to compare hand function and functional independence of such children with and without mirror movements. . METHODS: The comparative cross-sectional study was conducted in special education schools of Lahore and Islamabad from August 2017 to January 2018, and comprised children of either gender aged 5-18 years diagnosed with spastic cerebral palsy who were able to make a gross grip. Wood and Teuber criteria for the assessment of mirror movements and Jebsen-Taylor hand function test for hand function assessment were used, while manual ability classification system was used for the assessment of functional independence. Data was analysed using SPSS 21. RESULTS: Of the140 subjects, 113(80.7%) were boys and 27(19.3%) were girls. The overall mean age was 11.17}3.69 years. Of the total, 51(36.4%) subjects had diplegic cerebral palsy, while 50(35.7%) were suffering from mirror movements. There was no difference in the unimanual hand function of children with and without mirror movements (p>0.05). However, children without mirror movements had more functional independence (p<0.001). CONCLUSIONS: Mirror movement was found in one third of the sample, and there was no difference in hand function in children with and without mirror movements.

Transmembrane mucin MUC13 distinguishes intraductal papillary mucinous neoplasms from non-mucinous cysts and is associated with high-risk lesions.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMN) are currently managed based on imaging characteristics and cyst fluid sampling. This study was designed to determine if MUC13, a glycoprotein aberrantly overexpressed in pancreatic adenocarcinoma, might aid in distinguishing high-risk lesions (high grade dysplasia/invasive disease) from low-grade lesions. METHODS: MUC13 immunohistochemical staining was performed on surgically resected formalin-fixed tissue specimens from 49 IPMNs and 23 non-mucinous cysts. Membranous MUC13 expression was measured by H-score, which quantifies staining intensity and the percentage of cells involved (range 0-300). RESULTS: MUC13 expression was detected in all IPMNs and was significantly greater than in non-mucinous cysts (median 210 vs 40, p < 0.001). MUC13 expression was similar among main (n = 26), branch (n = 15), and mixed (n = 8) duct lesions (median 210, 200, 225, respectively). The highest expression was observed in tumors with intestinal and pancreatobiliary histologic features (both median 225) and the lowest in gastric type lesions (median 200). MUC13 expression was significantly greater in high-risk lesions (n = 21) compared to those with low-grade dysplasia (n = 28) (median 250 vs 195, p < 0.001). CONCLUSION: MUC13 expression was significantly greater in high-risk IPMNs in this analysis. The preoperative assessment of MUC13 in cyst fluid samples warrants further investigation.

Soil-transmitted helminth infections in school children of three districts of Malakand region, Khyber Pakhtunkhwa, Pakistan.

Information on prevalence of soil-transmitted helminth (STH) infections among school children is scarce in Pakistan. This study was aimed to investigate the prevalence of soil-transmitted helminth in school children of three districts in, Khyber Pakhtunkhwa, Pakistan. A total of 300 stool samples were examined from August 2015 to August 2016 using direct smear (Normal saline and Lugol's Iodine solution) and the concentration methods. One hundred and eighty seven (62.3%) pupils were found infected with soil-transmitted helminths. One hundred and forty five (77.5%) were infected with single parasite and forty two (22.4%) with multiple infections. Ascaris lumbricoides 125 (66.4%), Trichuris trichura 50 (26.5%) and Ancylostoma duedenale 13 (6.91%) were detected. The children above 8 years in age were more parasitized than below 8 years (p=0.7832; P>0.05). Males were found more parasitized than females (p=0.9315; P>0.05). Children in lower Dir district were found more infected followed by Swat and upper Dir (P< 0.0001; p<0.05). No significant relationship was found among the examined and that of infected children for ages and sex in all the districts. Malakand division is an area with poor hygiene located in temperate zone near the border of Afghanistan and China. The prevalence of reported nematode parasites here compared with the same studies is unexpectedly high. These types of studies should continue time to time to know the hazardous nature of such parasitic infections for the betterment of the human health.

Clinical significance of MUC13 in pancreatic ductal adenocarcinoma.

BACKGROUND: Poor prognosis of pancreatic cancer (PanCa) is associated with lack of an effective early diagnostic biomarker. This study elucidates significance of MUC13, as a diagnostic/prognostic marker of PanCa. METHODS: MUC13 was assessed in tissues using our in-house generated anti-MUC13 mouse monoclonal antibody and analyzed for clinical correlation by immunohistochemistry, immunoblotting, RT-PCR, computational and submicron scale mass-density fluctuation analyses, ROC and Kaplan Meir curve analyses. RESULTS: MUC13 expression was detected in 100% pancreatic intraepithelial neoplasia (PanIN) lesions (Mean composite score: MCS = 5.8; AUC >0.8, P < 0.0001), 94.6% of pancreatic ductal adenocarcinoma (PDAC) samples (MCS = 9.7, P < 0.0001) as compared to low expression in tumor adjacent tissues (MCS = 4, P < 0.001) along with faint or no expression in normal pancreatic tissues (MCS = 0.8; AUC >0.8; P < 0.0001). Nuclear MUC13 expression positively correlated with nodal metastasis (P < 0.05), invasion of cancer to peripheral tissues (P < 0.5) and poor patient survival (P < 0.05; prognostic AUC = 0.9). Submicron scale mass density and artificial intelligence based algorithm analyses also elucidated association of MUC13 with greater morphological disorder (P < 0.001) and nuclear MUC13 as strong predictor for cancer aggressiveness and poor patient survival. CONCLUSION: This study provides significant information regarding MUC13 expression/subcellular localization in PanCa samples and supporting the use anti-MUC13 MAb for the development of PanCa diagnostic/prognostic test.

Cerebral venous thrombosis: continental disparities.

Cerebral venous thrombosis (CVT) usually accounts for < 1% of all strokes. Global disparity and diversity in their demographics, etiology, clinical features, radiological presentation, and mortality have not been previously explored. A systematic search was performed for publications in PubMed using key words "cerebral venous thrombosis," "Cerebral vein thrombosis," and "Cortical vein Thrombosis." A total of 600 relevant studies were abstracted with strict selection criteria, and a total of 7048 patient's data were used for the final analysis. The frequency and relative frequency statistics were used to describe the data. Cases reported were Europe-3152, Asia-2722, North America-852, Africa-122, Australia-121, and South America-79. Overall male to female ratio was 1:2.2; among clinical characteristics, headache was the most common symptom and hematological factors were the most common etiology. Location of the thrombosis was described mostly in the transverse sinus. Intercontinental differences in relation to demographics, etiology, clinical features, radiological presentation, and mortality were identified. CVT can have significant disparity in their demographics, etiology, clinical features, radiological presentation, and mortality when compared from one continent to other. It is important for the worldwide physicians to recognize these differences and to follow the most recent guidelines, diagnostic methods, and treatment to insure the best outcome and prognosis.

The roles of cellular nanomechanics in cancer.

The biomechanical properties of cells and tissues may be instrumental in increasing our understanding of cellular behavior and cellular manifestations of diseases such as cancer. Nanomechanical properties can offer clinical translation of therapies beyond what are currently employed. Nanomechanical properties, often measured by nanoindentation methods using atomic force microscopy, may identify morphological variations, cellular binding forces, and surface adhesion behaviors that efficiently differentiate normal cells and cancer cells. The aim of this review is to examine current research involving the general use of atomic force microscopy/nanoindentation in measuring cellular nanomechanics; various factors and instrumental conditions that influence the nanomechanical properties of cells; and implementation of nanoindentation methods to distinguish cancer cells from normal cells or tissues. Applying these fundamental nanomechanical properties to current discoveries in clinical treatment may result in greater efficiency in diagnosis, treatment, and prevention of cancer, which ultimately can change the lives of patients.

Nanoways to overcome docetaxel resistance in prostate cancer.

Prostate cancer is the most common non-cutaneous malignancy in American men. Docetaxel is a useful chemotherapeutic agent for prostate cancer that has been available for over a decade, but the length of the treatment and systemic side effects hamper compliance. Additionally, docetaxel resistance invariably emerges, leading to disease relapse. Docetaxel resistance is either intrinsic or acquired by adopting various mechanisms that are highly associated with genetic alterations, decreased influx and increased efflux of drugs. Several combination therapies and small P-glycoprotein inhibitors have been proposed to improve the therapeutic potential of docetaxel in prostate cancer. Novel therapeutic strategies that may allow reversal of docetaxel resistance include alterations of enzymes, improving drug uptake and enhancement of apoptosis. In this review, we provide the most current docetaxel reversal approaches utilizing nanotechnology. Nanotechnology mediated docetaxel delivery is superior to existing therapeutic strategies and a more effective method to induce P-glycoprotein inhibition, enhance cellular uptake, maintain sustained drug release, and improve bioavailability.

KNOWLEDGE OF DIABETIC COMPLICATIONS IN PATIENTS WITH DIABETES MELLITUS.

BACKGROUND: The prevalence of diabetes mellitus has risen exponentially over the last three decades, with resultant increase in morbidity and mortality mainly due to its complications. Limited data is available regarding the awareness and knowledge about these complications in our population. This study was carried out to evaluate the knowledge of diabetic complications in patients with diabetes mellitus. METHODS: This cross-sectional study was conducted in the Medical B Unit of Department of Medicine Khyber Teaching Hospital, Peshawar. All admitted diabetic patients above 15 years of age with duration of diabetes mellitus more than one year were included. RESULTS: Out of the 96 patients questioned, 58 were females and 38 were males. Mean age was 53.29 +/- 10.821 years while the mean duration of diabetes mellitus was 9.75 +/- 7.729 years. Of the total 76 (79.1%) of the patients were illiterate; 36 (37.50%) had good, 24 (25%) had average and 36 (37.50%) had poor knowledge about diabetic complications. Males and university graduate patients had slightly better knowledge. Between 50-60% patients were aware of different cardiac complications of diabetes mellitus. Awareness regarding other complications was foot ulcer/gangrene 70 (72.91%), poor wound healing 68 (70.83%), stroke 54 (56.25%), renal diseases 64 (66.66%), eye diseases 53 (55.20%), gastroparesis and other gastrointestinal problems 45 (46.87%), diabetic ketoacidosis 55 (57.29%), hypoglycaemia 50 (52.08%), lipid abnormalities 26 (27.08%) and symptoms of diabetic neuropathy ranging from 47-65%. CONCLUSIONS: Majority of diabetic patients are unaware of diabetic complications. Therefore, hospital and community based awareness programs should be launched to decrease the morbidity and mortality associated with diabetes mellitus.

CEACAM7 expression contributes to early events of pancreatic cancer.

BACKGROUND: The trends of pancreatic cancer (PanCa) incidence and mortality are on rising pattern, and it will be a second leading cause of cancer related deaths by 2030. Pancreatic ductal adenocarcinoma (PDAC), major form of PanCa, exhibits a grim prognosis as mortality rate is very close to the incidence rate, due to lack of early detection methods and effective therapeutic regimen. Considering this alarming unmet clinic need, our team has identified a novel oncogenic protein, carcinoembryonic antigen-related cell adhesion molecule 7 (CEACAM7), that can be useful for spotting early events of PDAC. METHODOLOGY: This study includes bioinformatics pre-screening using publicly available cancer databases followed by molecular biology techniques in PDAC progressive cell line panel and human tissues to evaluate CEACAM7 expression in early events of pancreatic cancer. RESULTS: PanCa gene and protein expression analysis demonstrated the significantly higher expression of CEACAM7 in PDAC, compared to other cancers and normal pancreas. Overall survival analysis demonstrated an association between the higher expression of CEACAM7 and poor patients' prognosis with high hazard ratio. Additionally, in a performance comparison analysis CEACAM7 outperformed S100A4 in relation to PDAC. We also observed an increase of CEACAM7 in PDAC cell line panel model. However, poorly differentiated, and normal cell lines did not show any expression. Human tissue analysis also strengthened our data by showing strong and positive IHC staining in early-stage tumors. CONCLUSION: Our observations clearly cite that CEACAM7 can serve as a potential early diagnostic and/or prognostic marker of PDAC and may also potentiate the sensitivity of the existing biomarker panel of PDAC. However, further studies are warranted to determine its clinical significance.

An integrated computational biology approach defines the crucial role of TRIP13 in pancreatic cancer.

Pancreatic cancer (PanCa) is one of the most aggressive forms of cancer and its incidence rate is continuously increasing every year. It is expected that by 2030, PanCa will become the 2nd leading cause of cancer-related deaths in the United States due to the lack of early diagnosis and extremely poor survival. Despite great advancements in biomedical research, there are very limited early diagnostic modalities available for the early detection of PanCa. Thus, understanding of disease biology and identification of newer diagnostic and therapeutic modalities are high priority. Herein, we have utilized high dimensional omics data along with some wet laboratory experiments to decipher the expression level of hormone receptor interactor 13 (TRIP13) in various pathological staging including functional enrichment analysis. The functional enrichment analyses specifically suggest that TRIP13 and its related oncogenic network genes are involved in very important patho-physiological pathways. These analyses are supported by qPCR, immunoblotting and IHC analysis. Based on our study we proposed TRIP13 as a novel molecular target for PanCa diagnosis and therapeutic interventions. Overall, we have demonstrated a crucial role of TRIP13 in pathogenic events and progression of PanCa through applied integrated computational biology approaches.

Integrative big transcriptomics data analysis implicates crucial role of MUC13 in pancreatic cancer.

Big data analysis holds a considerable influence on several aspects of biomedical health science. It permits healthcare providers to gain insights from large and complex datasets, leading to improvements in the understanding, diagnosis, medication, and restraint of pathological conditions including cancer. The incidences of pancreatic cancer (PanCa) are sharply rising, and it will become the second leading cause of cancer related deaths by 2030. Various traditional biomarkers are currently in use but are not optimal in sensitivity and specificity. Herein, we determine the role of a new transmembrane glycoprotein, MUC13, as a potential biomarker of pancreatic ductal adenocarcinoma (PDAC) by using integrative big data mining and transcriptomic approaches. This study is helpful to identify and appropriately segment the data related to MUC13, which are scattered in various data sets. The assembling of the meaningful data, representation strategy was used to investigate the MUC13 associated information for the better understanding regarding its structural, expression profiling, genomic variants, phosphorylation motifs, and functional enrichment pathways. For further in-depth investigation, we have adopted several popular transcriptomic methods like DEGseq2, coding and non-coding transcript, single cell seq analysis, and functional enrichment analysis. All these analyzes suggest the presence of three nonsense MUC13 genomic transcripts, two protein transcripts, short MUC13 (s-MUC13, non-tumorigenic or ntMUC13), and long MUC13 (L-MUC13, tumorigenic or tMUC13), several important phosphorylation sites in tMUC13. Altogether, this data confirms that importance of tMUC13 as a potential biomarker, therapeutic target of PanCa, and its significance in pancreatic pathobiology.

Metagenomic analysis unveils the microbial landscape of pancreatic tumors.

The composition of resident microbes in the human body is linked to various diseases and their treatment outcomes. Although studies have identified pancreatic ductal adenocarcinoma (PDAC)-associated bacterial communities in the oral and gut samples, herein, we hypothesize that the prevalence of microbiota in pancreatic tumor tissues is different as compared with their matched adjacent, histologically normal appearing tissues, and these microbial molecular signatures can be highly useful for PDAC diagnosis/prognosis. In this study, we performed comparative profiling of bacterial populations in pancreatic tumors and their respective adjacent normal tissues using 16S rRNA-based metagenomics analysis. This study revealed a higher abundance of Proteobacteria and Actinomycetota in tumor tissues compared with adjacent normal tissues. Interestingly, the linear discriminant analysis (LDA) scores unambiguously revealed an enrichment of Delftia in tumor tissues, whereas Sphingomonas, Streptococcus, and Citrobacter exhibited a depletion in tumor tissues. Furthermore, we analyzed the microbial composition between different groups of patients with different tumor differentiation stages. The bacterial genera, Delftia and Staphylococcus, were very high at the G1 stages (well differentiated) compared with G2 (well to moderate/moderately differentiated) and G3/G4 (poorly differentiated) stages. However, the abundance of Actinobacter and Cloacibacterium was found to be very high in G2 and G3, respectively. Additionally, we evaluated the correlation of programmed death-ligand (PDL1) expression with the abundance of bacterial genera in tumor lesions. Our results indicated that three genera such as Streptomyces, Cutibacterium, and Delftia have a positive correlation with PD-L1 expression. Collectively, these findings demonstrate that PDAC lesions harbor relatively different microbiota compared with their normal tumor adjacent tissues, and this information may be helpful for the diagnosis and prognosis of PADC patients.

Synthesis and Antitumor Activity of Brominated-Ormeloxifene (Br-ORM) against Cervical Cancer.

Aberrant regulation of ß-catenin signaling is strongly linked with cancer proliferation, invasion, migration, and metastasis, thus, small molecules that can inhibit this pathway might have great clinical significance. Our molecular modeling studies suggest that ormeloxifene (ORM), a triphenylethylene molecule that docks with ß-catenin, and its brominated analogue (Br-ORM) bind more effectively with relatively less energy (-7.6 kcal/mol) to the active site of ß-catenin as compared to parent ORM. Herein, we report the synthesis and characterization of a Br-ORM by NMR and FTIR, as well as its anticancer activity in cervical cancer models. Br-ORM treatment effectively inhibited tumorigenic features (cell proliferation and colony-forming ability, etc.) and induced apoptotic death, as evident by pronounced PARP cleavage. Furthermore, Br-ORM treatment caused cell cycle arrest at the G1-S phase. Mechanistic investigation revealed that Br-ORM targets the key proteins involved in promoting epithelial-mesenchymal transition (EMT), as demonstrated by upregulation of E-cadherin and repression of N-cadherin, Vimentin, Snail, MMP-2, and MMP-9 expression. Br-ORM also represses the expression and nuclear subcellular localization of ß-catenin. Consequently, Br-ORM treatment effectively inhibited tumor growth in an orthotopic cervical cancer xenograft mouse model along with EMT associated changes as compared to vehicle control-treated mice. Altogether, experimental findings suggest that Br-ORM is a novel, promising ß-catenin inhibitor and therefore can be harnessed as a potent anticancer small molecule for cervical cancer treatment.

MUC13 drives cancer aggressiveness and metastasis through the YAP1-dependent pathway.

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.

A novel cyano derivative of 11-keto-ß-boswellic acid causes apoptotic death by disrupting PI3K/AKT/Hsp-90 cascade, mitochondrial integrity, and other cell survival signaling events in HL-60 cells.

Intervention of apoptosis is a promising strategy for discovery of novel anti-cancer therapeutics. In this study, we examined the ability of a novel cyano derivative of 11-keto-ß-boswellic acid, that is, butyl 2-cyano-3,11-dioxours-1,12-dien-24-oate (BCDD) to induce apoptosis in cancer cells. BCDD inhibited cell proliferation with 48 h IC(50) of 0.67 µM in HL-60, 1 µM in Molt4, and 1.5 µM in THP1 cells. The mechanism of cell death was investigated in HL-60 cells where it caused apoptosis by acting against several potential apoptosis suppressive targets. It inhibited phosphatidylinositol-3-kinase (PI3K)/AKT activity, NF-κB, Hsp-90, and survivin which may enhance the sensitivity of cells to apoptosis. Also, BCDD decreased the activity of Bid and Bax in cytosol, caused ΔΨ(mt) loss, releasing pro-apoptotic cytochrome c, SMAC/DIABLO leading to caspase-9-mediated down stream activation of caspase-3, ICAD, and PARP1 cleavage. Translocation of apoptotis-inducing factor (AIF) from mitochondria to the nucleus indicated some caspases-independent apoptosis. Though it upregulated DR-5 and caspase-8, the caspase inhibitor yet had no effect on apoptosis as against 75% inhibition by caspase-9 inhibitor. Attempts were made to examine any acclaimed role of AIF in the activation of caspase-8 using siRNA where it had no effect on caspase-8 activity while the Bax-siRNA inhibited caspase-3 activation suggesting predominance of intrinsic signaling. Our studies thus demonstrated that BCDD exerts multi-focal action in cancer cells while it required 10-fold higher the concentration to produce cytotoxicity in normal human PBMC and gingival cell line, and therefore, may find usefulness in the management of human leukemia.