Chemopreventive Drugs Research Articles

Folated curcumin-gold nanoformulations: A nanotherapeutic strategy for breast cancer therapy

Breast cancer is considered a leading health problem, especially in women, and is a major contributor to the annual worldwide cancer mortality rate. Various drawbacks and a range of side effects are faced by cancer patients undergoing the conventional cancer therapy methods that do not always result in positive and successful outcomes. Current research introducing nanomaterials into in vivo breast cancer therapy applications has revolutionized various aspects of these therapies. These include conjugating natural compounds onto nanoparticles (NPs) such as curcumin that exhibit chemopreventive activity, and controlled drug release targeting specific organs or tumor sites, thereby reducing the side effects otherwise caused by conventional cancer therapy. Recently, folate-tagged gold nanoparticles (AuNPs) are proving to be the leading nanocarriers used in cancer treatment and detection and can also be combined with different therapies such as chemotherapy, radiotherapy, and photothermal therapy. The development of such nano-based systems possessing enzyme mimetic properties, blood compatibility, and the ability to differentiate between normal cells and cancer cell properties deems them suitable for in vivo applications and have attracted enormous attention for devising early detection and diagnosis for breast cancer. In this review, we will discuss recent progress in the use of curcumin as a chemopreventive drug in cancer therapy and review the different routes in use for the synthesis and functionalization of Au NPs. Finally, we will review the current state of research with respect to curcumin and folic acid-conjugated Au NPs and their applications in detection, diagnosis, and treatment of breast cancer.

Targeting STAT proteins via computational analysis in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide making it a serious global challenge. CRC progression results from dysregulated cytoplasmic transcription factors, including signal transducer and activator of transcription (STAT) proteins that are involved in JAK-STAT pathway. The STAT proteins contain a conserved SH2 domain that facilitates the initiation of STAT activation via binding to tyrosine motifs followed by STAT dimerization. The STAT proteins include STAT1, STAT2 and STAT3 which all facilitate therapeutic targets for many drugs, since they are associated with pathogenesis in various cancers such as CRC. Genistein is an efficient chemopreventive phytochemical drug against CRC. The current investigation presents a computational study performed to investigate the molecular interaction between STAT1, STAT2 and STAT3 proteins with genistein. The molecular dynamic simulation was conducted for STAT2 protein. The studies from molecular docking revealed that the interaction of STAT proteins and genistein is predicted to be effective with better binding energies. Furthermore, targeting STAT3 could be an efficient therapeutic target and understanding the interaction between STAT3 and genistein can help to contribute to a better inhibition process for CRC progression. Treatment with genistein led to significant suppression of cell proliferation and STAT3 protein expression in both CRC (HCT 116 and HT-29) cell lines. This further provides development of efficient STAT inhibitors with better potency and bioavailability.

Abstract 1443: Inhibiting HMG-CoA reductase suppresses non-small cell lung carcinogenesis

Abstract 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) is a rate-limiting enzyme in the mevalonate pathway and is associated with the development of several tumor types. However, the role of HMGCR in non-small cell lung cancer (NSCLC) is still unknown. In the present study, we found that HMGCR is overexpressed in human lung adenocarcinoma tissues compared with normal tissues. Knockdown of HMGCR in NSCLC cells attenuated growth and induced apoptosis in vitro and in vivo. Furthermore, we found that fluvastatin, an inhibitor of HMGCR, suppressed NSCLC cell growth and induced apoptosis. Intriguingly, fluvastastin functions by inhibiting the HMGCR-driven Braf/MEK/ERK1/2 and Akt signaling pathways. Notably, fluvastatin attenuated tumor growth in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis and in a patient-derived xenograft (PDX) lung tumor model. Overall, our findings suggest that fluvastatin might be promising chemopreventive or potential therapeutic drug against NSCLC tumorigenesis, providing hope for rapid clinical translation. Citation Format: Qiushi Wang, Tianshun Zhang, Ruihua Bai, Keke Wang, Xiang Li, Kangdong Liu, Ting Wang, Xiaoyu Chang, Weiya Ma, Ann Bode, Qingxin Xia, Yongping Song, Zigang Dong. Inhibiting HMG-CoA reductase suppresses non-small cell lung carcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1443.

Abstract 6380: Suppression of the solar ultraviolet-induced skin carcinogenesis by TOPK inhibitor HI-TOPK-032

Abstract Non-melanoma skin cancer (NMSC) such as cutaneous squamous cell carcinoma (cSCC) is caused by solar ultraviolet (SUV) exposure and is the most common cancer in the United States. T-LAK cell-originated protein kinase (TOPK), a serine-threonine kinase is activated by SUV irradiation and involved in skin carcinogenesis. Strategies with research focusing on the TOPK signaling pathway and targeted therapy in skin carcinogenesis may helpful for the discovery of additional treatments against skin cancer. In this study, we found that TOPK can directly bind to and phosphorylate c-Jun (as one of the core member of AP-1) at Ser63 and Ser73 after SSL exposure in a JNKs-independent manner. TOPK knocking down, or HI-TOPK-032 (TOPK specific inhibitor) attenuated colony formation and cell proliferation of skin cancer cells. Phosphorylated levels of c-Jun were overexpressed in human AK and cSCC compared to normal skin tissues, and HI-TOPK-032 inhibited the phosphorylation of c-Jun in SCC cell line in a dose-dependent manner. Furthermore, HI-TOPK-032 decreased SSL-induced AP-1 transactivation activity. Moreover, acute SSL-induced inflammation was attenuated by the topical application of HI-TOPK-032 in SKH1 hairless mice. Importantly, HI-TOPK-032 suppressed chronic SSL-induced skin carcinogenesis and c-Jun phosphorylation levels in SKH1 hairless mice. Our results demonstrate that TOPK can phosphorylate and activate c-Jun at Ser63 and Ser73 in the process of skin carcinogenesis and HI-TOPK-032 could be used as a potential chemopreventive drug against cSCC development. Citation Format: Eunmiri Roh, Yaping Han, Kanamata Reddy, Tatyana A. Zykova, Mee Hyun Lee, Ke Yao, Ruihua Bai, Clara Curiel-Lewandrowski, Zigang Dong. Suppression of the solar ultraviolet-induced skin carcinogenesis by TOPK inhibitor HI-TOPK-032 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6380.

Abstract B36: Antimalarial agent, atovaquone, inhibits cancer cell proliferation by targeting oxidative phosphorylation and is a candidate for chemoprevention and chemotherapy of ovarian cancer

Abstract Atovaquone is a FDA-approved antimalarial agent that has also shown potent anticancer properties. In the current study, we demonstrate that atovaquone is a prime candidate for treatment of high-grade serous ovarian cancer. We have tested atovaquone against a panel of ovarian cancer cells lines and shown that this drug inhibits proliferation and induces apoptosis at IC50 concentrations between 10-20 microM. Exposure to atovaquone results in increased apoptosis as indicated by an increase in cleaved caspase 3 and other relevant apoptotic markers. Additionally, our data also suggest that atovaquone is able to reactivate p53. Inhibition of p53 attenuates the cytotoxicity of atovaquone. However, the primary event that occurs in atovaquone-treated cells is the rapid surge in intracellular oxygen radicals. Imaging cytometry experiments conclusively demonstrate that the oxygen radical surge originates in the mitochondria. The oxidative stress caused by atovaquone is responsible for DNA damage and p53 activation. The atovaquone-induced oxygen radical surge also leads to damage to the Na+/K+-ATPase, perturbing the ability of the cancer cells to maintain an optimal membrane potential. This increase in oxygen radicals occurs because atovaquone targets the oxidative phosphorylation pathway in the mitochondria and blocks electron transport. Measurements conducted on the Seahorse analyzer show decreased consumption of oxygen and lower levels of ATP in the atovaquone-treated cells. In the malarial parasite, atovaquone targets mitochondrial complex III. In ovarian cancer cells, supplying succinate did not reverse atovaquone-induced inhibition of oxidative phosphorylation. On the other hand, when cells were supplemented with the substrate for complex IV, the oxygen consumption rate normalized in atovaquone-exposed cells. These experiments suggest that atovaquone is likely inhibiting complex I-III of mitochondria. Atovaquone is a naphthoquinone with significant structural similarity with the electron transporter ubiquinone. In silico modeling experiments indicate that atovaquone can bind to the ubiquinone binding pocket on complexes I-III. Based on these experiments, we propose that atovaquone is competing with ubiquinone to inhibit efficient electron transport and thereby increasing the intracellular oxygen radicals. Ovarian tumor-bearing mice tolerated prolonged treatment with Mepron®, the clinical formulation of atovaquone. Daily treatment of ID8 tumor-bearing C57BL/6 mice with atovaquone for 3-4 weeks resulted in a significant decrease in tumor growth. Additionally, we also show decreased proliferation of human ovarian tumors treated ex vivo with atovaquone. These experiments indicate that atovaquone can be used as a safe and effective drug for chemoprevention and chemotherapy of ovarian tumors. Citation Format: Arvinder Kapur, Mildred Felder, Yousef Alharbi, Allegra Cappuccini, Bikash Pattnaik, Lisa Barroilhet, Manish Patankar. Antimalarial agent, atovaquone, inhibits cancer cell proliferation by targeting oxidative phosphorylation and is a candidate for chemoprevention and chemotherapy of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B36.

Antioxidant and antiproliferative activities on prostate and cervical cultured cancer cells of five medicinal plant extracts from Burkina Faso

Medicinal plants are a potential source of drug discovery and development of cancer chemoprevention drugs. Thus, the aim of this work was to study the antioxidant and antiproliferative activities of hydromethanolic extracts of Musa sapientum L., Cassia italica (Mill.) Spreng., Crateva adansonii DC., Euphorbia hirta L. and Ceratotheca sesamoides Endl. from Burkina Faso. The antioxidative activity of hydromethanolic extracts of plant was assessed using DPPH radical scavenging assay and ABTS+ radical cation decolorisation assay. Antiproliferative activity was evaluated by MTT assay. Of these five plant extracts, hydromethanolic extract of Euphorbia hirta leaf twigs showed the best antioxidant activity both by DPPH (IC50 = 0.53 ± 0.04 μg extract / μg DPPH) and ABTS (C = 0.302 ± 0.003 μMET / g extract) methods. In addition, hydromethanolic extract of Euphorbia hirta leaf twigs showed the best antiproliferative activity on LNCaP cell lines of prostate cancer while the hydromethanolic extract of the Ceratotheca sesamoides leaf stems showed the best antiproliferative activity on the HeLa cell lines of cervical cancer. This work has shown not only the antioxidant and anticancer activities of these five local plants, but also the potential valorization of these species used in traditional medicine in Burkina Faso.Keywords: Cancer, antioxydant, antiproliferative, Medicinal plants, Burkina Faso.

Role of Using Nonsteroidal Anti-Inflammatory Drugs in Chemoprevention of Colon Cancer in Patients With Inflammatory Bowel Disease.

The process of inflammation occurs due to inflammatory mediators, including prostaglandins, cytokines, and tumor necrosis factor (TNF). All these mediators activate the process of tumorigenesis and dysplasia, leading to colitis-associated cancer. Several drugs used to decrease these mediators will help in the treatment of acute attacks and also help in prolonged remissions of the disease by using nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, and biological factors. Reducing these inflammatory mediators also have a role in chemoprevention and prevent progression to colorectal carcinoma. The most researched drugs in this process of chemoprevention are NSAIDs as it has both cyclooxygenase-2 (COX-2) inhibitory and non-inhibitory effects. These drugs should be taken for a long time and in large doses to reach this effect, which puts the patient at risk for various side effects. Researchers will need to do more research in the future to find the lowest effective dose that can reach the chemopreventive effect. We used database Pubmed as the main source for data search and extracted articles exploring the relationship between NSAIDs and their role in chemoprevention of colorectal carcinoma in inflammatory bowel disease (IBD) patients. We chose 23 studies which included seven review articles. We found that inflammatory mediators have a key role in colitis-associated cancer.

Suppression of the solar ultraviolet-induced skin carcinogenesis by TOPK inhibitor HI-TOPK-032.

Nonmelanoma skin cancer (NMSC) such as cutaneous squamous cell carcinoma (cSCC) is caused by solar ultraviolet (SUV) exposure and is the most common cancer in the United States. T-LAK cell-originated protein kinase (TOPK), a serine-threonine kinase is activated by SUV irradiation and involved in skin carcinogenesis. Strategies with research focusing on the TOPK signaling pathway and targeted therapy in skin carcinogenesis may helpful for the discovery of additional treatments against skin cancer. In this study, we found that TOPK can directly bind to and phosphorylate c-Jun (as one of the core member of AP-1) at Ser63 and Ser73 after SSL exposure in a JNKs-independent manner. TOPK knocking down, or HI-TOPK-032 (TOPK specific inhibitor) attenuated colony formation and cell proliferation of skin cancer cells. Phosphorylated levels of c-Jun were overexpressed in human AK and cSCC compared with normal skin tissues, and HI-TOPK-032 inhibited the phosphorylation of c-Jun in SCC cell line in a dose-dependent manner. Furthermore, HI-TOPK-032 decreased SSL-induced AP-1 transactivation activity. Moreover, acute SSL-induced inflammation was attenuated by the topical application of HI-TOPK-032 in SKH1 hairless mice. Importantly, HI-TOPK-032 suppressed chronic SSL-induced skin carcinogenesis and c-Jun phosphorylation levels in SKH1 hairless mice. Our results demonstrate that TOPK can phosphorylate and activate c-Jun at Ser63 and Ser73 in the process of skin carcinogenesis and HI-TOPK-032 could be used as a potential chemopreventive drug against cSCC development.

Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

BackgroundDrug safety assessments in clinical trials present unique analytical challenges. Some of these include adjusting for individual follow-up time, repeated measurements of multiple outcomes and missing data among others. Furthermore, pre-specifying appropriate analysis becomes difficult as some safety endpoints are unexpected. Although existing guidelines such as CONSORT encourage thorough reporting of adverse events (AEs) in clinical trials, they provide limited details for safety data analysis. The limited guidelines may influence suboptimal analysis by failing to account for some analysis challenges above. A typical example where such challenges exist are trials of anti-malarial drugs for malaria prevention during pregnancy. Lack of proper standardized evaluation of the safety of antimalarial drugs has limited the ability to draw conclusions about safety. Therefore, a systematic review was conducted to establish the current practice in statistical analysis for preventive antimalarial drug safety in pregnancy.MethodsThe search included five databases (PubMed, Embase, Scopus, Malaria in Pregnancy Library and Cochrane Central Register of Controlled Trials) to identify original English articles reporting Phase III randomized controlled trials (RCTs) on anti-malarial drugs for malaria prevention in pregnancy published from January 2010 to July 2019.ResultsEighteen trials were included in this review that collected multiple longitudinal safety outcomes including AEs. Statistical analysis and reporting of the safety outcomes in all the trials used descriptive statistics; proportions/counts (n = 18, 100%) and mean/median (n = 2, 11.1%). Results presentation included tabular (n = 16, 88.9%) and text description (n = 2, 11.1%). Univariate inferential methods were reported in most trials (n = 16, 88.9%); including Chi square/Fisher’s exact test (n = 12, 66.7%), t test (n = 2, 11.1%) and Mann–Whitney/Wilcoxon test (n = 1, 5.6%). Multivariable methods, including Poisson and negative binomial were reported in few trials (n = 3, 16.7%). Assessment of a potential link between missing efficacy data and safety outcomes was not reported in any of the trials that reported efficacy missing data (n = 7, 38.9%).ConclusionThe review demonstrated that statistical analysis of safety data in anti-malarial drugs for malarial chemoprevention in pregnancy RCTs is inadequate. The analyses insufficiently account for multiple safety outcomes potential dependence, follow-up time and informative missing data which can compromise anti-malarial drug safety evidence development, based on the available data.

Wu Mei Wan attenuates CAC by regulating gut microbiota and the NF-kB/IL6-STAT3 signaling pathway

BackgroundColorectal cancer (CRC) has a high incidence and mortality rate worldwide. Colitis-associated CRC (CAC) is used for describing the relationship between inflammation and CRC. No chemopreventive agents have been found to be both effective and safe in CRC. Therefore, the prevention and treatment of CAC are extremely urgent. Wu Mei Wan (WMW) has been used for the clinical treatment of enteritis with a remarkable efficacy. Here, we aim to investigate the underlying mechanism of WMW in the prevention of CAC. MethodsThe AOM/DSS-induced CAC mouse model was used, and the mice were divided into normal control (NC), AOM/DSS model control (MC), and AOM/DSS plus WMW (WMW). The weight of mice, the score of DAI, survival rate, number of tumors and sample collection were performed at the end of the 14th week. Histopathological examination was performed using Hematoxylin–Eosin (HE) staining. Tumor cell proliferation was indicated by the expression of PCNA, and p65 and p-STAT3 were detected by immunohistochemistry. Serum IL-6 levels were detected by enzyme-linked immunosorbent assay (ELISA). The expression of p65, IL-6 and p-STAT3 in the colon was detected by Western Blot. Intestinal flora was analyzed by 16S rDNA sequencing. ResultsWMW improved the survival rate of mice in the MC group and also attenuated CAC symptoms such as abnormal clinical colitis and pathological changes to intestinal tissue by reducing DAI score, tumor formation, tumor volume, and grade of tumorigenesis. WMW also reduced the proliferation of tumor cells in colon tissues. WMW decreased the expression of p65, IL-6, and p-STAT3 in colon tumors of CAC mice. WMW decreased Bacteroidetes and increased Firmicutes at the phylum level, while decreasing bacteroidales_s24-7_group and increasing the number of Lachnospiraceae at the family level. ConclusionWMW attenuates CAC by regulating the balance between “tumor-promoting bacteria” and “tumor-suppressing bacteria” and the NF-kB/IL-6/STAT3 pathway. WMW has the potential to be a safe and effective chemopreventive drug but further clinical evidence is necessary.

Anti-cancer Effects of Azadirachta indica in Diethylnitrosamine-Induced Hepatocellular Carcinoma in Wistar Rats

Hepatocellular carcinoma (HCC) is a primary liver cancer and has a high rate of mortality. Exploration of local herbal as a chemo-preventive drug has been conducted. This present study aimed to observe the anti-cancer effect of hydroethanolic extracts of Azadirachta indica both Indonesia (HEAII) and the Philippines (HEAIP) on diethylnitrosamine (DEN)-induced HCC on Wistar rat model. VEGF/FGF2/CD166/YAP were evaluated using immunohistochemistry. VEGF/FGF2/CD166/YAP were down-regulated in HCC treated with HEAII and HEAIP compare to that non-treatment HCC. Liver function (aminotransferase (AST) and aminotransferase (ALT) activities) was evaluated from serum. Value of AST and ALT were abnormal in the non-treatment HCC and normal in the HCC treated. These results indicated that both extracts were found to possess anti-cancer activity in HCC.

A numerical simulation study of the dual role of [formula omitted]-reductase inhibitors on tumor growth in prostates enlarged by benign prostatic hyperplasia via stress relaxation and apoptosis upregulation

5α-reductase inhibitors are regarded as a promising chemoprevention strategy to reduce the incidence and delay the progression of prostate cancer. Landmark clinical trials have shown the chemopreventive potential of these drugs, but they appear to be mostly effective in mild tumors and have also been correlated with a higher prevalence of advanced prostate cancer. Hence, the use of 5α-reductase inhibitors for prostate cancer chemoprevention has become a controversial issue. The effects of these drugs on prostate cancer growth remain incompletely understood, but they are thought to promote apoptosis in the tumor. Additionally, 5α-reductase inhibitors induce global prostate shrinkage, which decreases the tumor-inhibiting effect of the mechanical stress accumulated in prostatic tissue due to common prostate enlargement with age. Thus, the competition between this mechanical effect and apoptotic upregulation may explain the controversial outcomes of 5α-reductase inhibitors on prostate cancer. Here, we extend our mechanically-coupled model of prostate cancer growth by including the mechanical and apoptotic action of 5α-reductase inhibitors and explore their combined effect on an aggressive tumor in silico. Our simulations show that the apoptotic boost dominates in the first months of therapy but the long-term outcome of 5α-reductase inhibitors depends on its competition with a decrease in hydrostatic stress caused by prostate shrinkage, which favors tumor growth. By combining moderate or strong prostate shrinkage with mild or intense apoptotic upregulation, our simulations show different tumor growth dynamics ranging from long-term inhibition of prostate cancer growth to rapidly growing large tumors, which may evolve towards advanced disease. Thus, our proposed mechanism for the action of 5α-reductase inhibitors may contribute to resolve the controversy around the use of these drugs for chemoprevention and to gain insight on prostate cancer dynamics during its use. The computational technology used herein could also assist physicians to monitor prostatic tumors during 5α-reductase inhibitor therapy and enable the early identification of responders from non-responders in a patient-specific manner.

Radial Profile Analysis of Epithelial Polarity in Breast Acini: A Tool for Primary (Breast) Cancer Prevention.

Preventing cancer is vastly better than treating the disease in terms of a patient's quality of life and healthcare costs. Yet, to screen for chemopreventative drugs or evaluate interventions aimed at lowering cancer risk, quantitative readouts of risk are needed. In the breast and in other organs of epithelial origin, apical-basal polarity is key to homeostasis and is one of the first tissue characteristics lost during cancer initiation. Therefore, apical-basal polarity may be leveraged as an “architectural” determinant of cancer risk. A classic approach to quantify the localization of epithelial polarity markers is visual scoring at the microscope by trained investigators. This approach is time-intensive and limited to low throughput. To increase the speed, accuracy, and scoring volume, we developed an algorithm that essentially replaces the human eye to objectively quantify epithelial polarity in microscopy images of breast glandular units (acini). Acini in culture are identified based on a nuclear stain and the corresponding masks are divided into concentric terraces of equal width. This positional information is used to calculate radial intensity profiles (RP) of polarity markers. Profiles with a steep slope represent polarized structures, whereas more horizontal curves are indicative of non-polarized acini. To compare treatment effects, RP curves are integrated into summary values of polarity. We envision applications of this method for primary cancer prevention research with acini organoids, specifically (1) to screen for chemoprevention drugs, (2) for toxicological assessment of suspected carcinogens and pharmacological hit compounds, and (3) for personalized evaluation of cancer risk and risk-reducing interventions. The RadialProfiler algorithm developed for the MATLAB computing environment and for users without prior informatics knowledge is publicly available on the Open Science Framework (OSF).

Sulforaphane in broccoli: The green chemoprevention!! Role in cancer prevention and therapy

Isothicyanates present in cruciferous vegetables are known to exhibit chemoprevention by various mechanisms. Presently, there is growing evidence that a phytochemical compound known as sulforaphane in these green leafy vegetables is found to be effective in preventing and treating various cancers such as prostate cancer, breast cancer, colon cancer, skin, urinary bladder and oral cancers. This component is naturally present in the broccoli sprouts, kale, cabbage, cauliflower and garden cress and is available as a commercial supplementary pill called Broccoli extract. Availability of many bioactive substances such as vitamins, polyphenols, sulfides, glucosinolates and antioxidants makes broccoli consumption important in daily diet regularly. Researchers have named it as “Green chemoprevention.” It is easily affordable and more cost-effective than the traditional chemopreventive drugs. Results from the epidemiological and experimental studies have emphasized the role of sulforophane as a complementary or alternative chemopreventive agent.

Extracellular vesicles in biological fluids. A biomarker of exposure to cigarette smoke and treatment with chemopreventive drugs.

SummaryExtracellular vesicles (EVs) are released from cells and enter into body fluids thereby providing a toxicological mechanism of cell-cell communication. The present study aimed at assessing (a) the presence of EVs in mouse body fluids under physiological conditions, (b) the effect of exposure of mice to cigarette smoke for 8 weeks, and (c) modulation of smoke-related alterations by the nonsteroidal anti-inflammatory drug celecoxib, a selective cyclooxygenase-2 inhibitor. To this purpose, ICR (CD-1) mice were either unexposed or exposed to cigarette smoke, either treated or untreated with oral celecoxib. EVs, isolated from bronchoalveolar lavage fluid (BALF), blood serum, and urines, were analyzed by nanoparticle tracking analysis and flow cytometry. EVs baseline concentrations in BALF were remarkably high. Larger EVs were detected in urines. Smoking increased EVs concentrations but only in BALF. Celecoxib remarkably increased EVs concentrations in the blood serum of both male and female smoking mice. The concentration of EVs positive for EpCAM, a mediator of cell-cell adhesion in epithelia playing a role in tumorigenesis, was much higher in urines than in BALF, and celecoxib significantly decreased their concentration. Thus, the effects of smoke on EVs concentrations were well detectable in the extracellular environment of the respiratory tract, where they could behave as delivery carriers to target cells. Celecoxib exerted both protective mechanisms in the urinary tract and adverse systemic effects of likely hepatotoxic origin in smoke-exposed mice. Detection of EVs in body fluids may provide an early diagnostic tool and an end-point exploitable for preventive medicine strategies.

Curcumin inhibited the growth and invasion of human monocytic leukaemia SHI-1 cells in vivo by altering MAPK and MMP signalling

Context Curcumin, a polyphenolic compound extracted from the rhizome of the tropical plant Curcuma longa L. (Zingiberaceae), has been considered as a cancer chemopreventive drug by American National Cancer Institute. Objective To examine the effect of curcumin on acute monocytic leukaemia SHI-1 cells in vivo. Materials and methods The SHI-1 cells (1 × 106 cells in 0.1 mL PBS) were injected subcutaneously into the right flanks of the female SCID mice. Curcumin dissolved in olive oil (15 and 30 mg/kg) was administered (i.p.) to mice once a day for 15 days while the control group received olive oil injection. Tumour proliferation and apoptosis were examined by PCNA, TUNEL and cleaved caspase-3 staining. The expression of MAPK, NF-κB, MMP9, MMP2 and vimentin were confirmed by RT-PCR, immunohistochemistry or western blotting. Results Administration of curcumin significantly inhibited tumour growth, as the tumour weight decreased from 0.67 g (control) to 0.47 g (15 mg/kg) and 0.35 g (30 mg/kg). Curcumin inhibited the expression of PCNA and increased the degree of TUNEL and cleaved caspase-3 staining in tumour tissue. The results of western blotting showed that curcumin treatment inhibited NF-κB and ERK signalling while activating p38 and JNK. Moreover, curcumin attenuated the mRNA transcription and protein expression of MMP2 and MMP9. Curcumin also suppressed the level of vimentin. Discussion and conclusions Our study demonstrates that curcumin can inhibit the growth and invasion of human monocytic leukaemia in vivo, suggesting the possible use of curcumin for anti-metastasis in leukaemia and the value of determining its unique target.

Chromosome fragility in the buccal epithelium in patients with Fanconi anemia.

Fanconi anemia (FA) is a rare genome instability syndrome characterized by progressive bone marrow failure and predisposition to cancer, especially head and neck squamous cell carcinoma. Surgical resection is the standard of care for solid tumors, as patients with FA do not tolerate genotoxic chemotherapies or radiation, leading to poor prognosis. It is therefore imperative to develop chemoprevention strategies such as the identification of novel biomarkers to detect the formation of the tumor before its emergence and to use them in clinical trials aimed to counteract genome instability of patients with FA in tissues at risk. Micronuclei (MN) are chromosome fragments that are left behind in anaphase and appear in daughter cells as small additional nuclei. In this work, we analyzed MN frequencies in exfoliated buccal cells from 40 patients with FA and 24 controls. We found that MN frequency was significantly increased in the FA cohort indicating that we can detect chromosome fragility in patients with FA in basal conditions and in a tissue that is divided in vivo. Consequently, the MN assay in exfoliated buccal cells of patients with FA could be used in cancer risk studies and clinical trials aimed to identify cancer chemopreventive drugs.

Fluvastatin Inhibits HMG-CoA Reductase and Prevents Non-Small Cell Lung Carcinogenesis.

Lung cancer is the leading cause of cancer-related death worldwide. However, promising agents for lung cancer prevention are still very limited. Identification of preventive targets and novel effective preventive agents is urgently needed for clinical applications. In this study, we found that fluvastatin targeted 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), which a rate-limiting enzyme in the mevalonate pathway, and inhibited non-small cell lung cancer (NSCLC) tumorigenesis. Initially, we demonstrated that HMGCR is overexpressed in human lung adenocarcinoma tissues compared with normal tissues. Knockdown of HMGCR in NSCLC cells attenuated growth and induced apoptosis in vitro and in vivo Furthermore, we found that fluvastatin, an inhibitor of HMGCR, suppressed NSCLC cell growth and induced apoptosis. Intriguingly, fluvastastin functions by inhibiting the HMGCR-driven Braf/MEK/ERK1/2 and Akt signaling pathways. Notably, fluvastatin attenuated tumor growth in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis and in a patient-derived xenograft lung tumor model. Overall, our findings suggest that fluvastatin might be promising chemopreventive or potential therapeutic drug against NSCLC tumorigenesis, providing hope for rapid clinical translation.

Cellular Stress-Modulating Drugs Can Potentially Be Identified by in Silico Screening with Connectivity Map (CMap).

Accompanied by increased life span, aging-associated diseases, such as metabolic diseases and cancers, have become serious health threats. Recent studies have documented that aging-associated diseases are caused by prolonged cellular stresses such as endoplasmic reticulum (ER) stress, mitochondrial stress, and oxidative stress. Thus, ameliorating cellular stresses could be an effective approach to treat aging-associated diseases and, more importantly, to prevent such diseases from happening. However, cellular stresses and their molecular responses within the cell are typically mediated by a variety of factors encompassing different signaling pathways. Therefore, a target-based drug discovery method currently being used widely (reverse pharmacology) may not be adequate to uncover novel drugs targeting cellular stresses and related diseases. The connectivity map (CMap) is an online pharmacogenomic database cataloging gene expression data from cultured cells treated individually with various chemicals, including a variety of phytochemicals. Moreover, by querying through CMap, researchers may screen registered chemicals in silico and obtain the likelihood of drugs showing a similar gene expression profile with desired and chemopreventive conditions. Thus, CMap is an effective genome-based tool to discover novel chemopreventive drugs.

Streptomyces sp. MUM256: A Source for Apoptosis Inducing and Cell Cycle-Arresting Bioactive Compounds against Colon Cancer Cells.

New and effective anticancer compounds are much needed as the incidence of cancer continues to rise. Microorganisms from a variety of environments are promising sources of new drugs; Streptomyces sp. MUM256, which was isolated from mangrove soil in Malaysia as part of our ongoing efforts to study mangrove resources, was shown to produce bioactive metabolites with chemopreventive potential. This present study is a continuation of our previous efforts and aimed to investigate the underlying mechanisms of the ethyl acetate fraction of MUM256 crude extract (MUM256 EA) in inhibiting the proliferation of HCT116 cells. Our data showed that MUM256 EA reduced proliferation of HCT116 cells via induction of cell-cycle arrest. Molecular studies revealed that MUM256 EA regulated the expression level of several important cell-cycle regulatory proteins. The results also demonstrated that MUM256 EA induced apoptosis in HCT116 cells mediated through the intrinsic pathway. Gas chromatography-mass spectrometry (GC-MS) analysis detected several chemical compounds present in MUM256 EA, including cyclic dipeptides which previous literature has reported to demonstrate various pharmacological properties. The cyclic dipeptides were further shown to inhibit HCT116 cells while exerting little to no toxicity on normal colon cells in this study. Taken together, the findings of this project highlight the important role of exploring the mangrove microorganisms as a bioresource which hold tremendous promise for the development of chemopreventive drugs against colorectal cancer.