Chemopreventive Role Research Articles

Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription regulator that plays a pivotal role in coordinating the cellular response to oxidative stress. Through interactions with other proteins, such as Kelch-like ECH-associated protein 1 (Keap1), CREB-binding protein (CBP), and retinoid X receptor alpha (RXRα), Nrf2 mediates the transcription of cytoprotective genes critical for removing toxicants and preventing DNA damage, thereby playing a significant role in chemoprevention. Dysregulation of Nrf2 is linked to tumorigenesis and chemoresistance, making Nrf2 a promising target for anticancer therapeutics. However, despite the physiological importance of Nrf2, the molecular details of this protein and its interactions with most of its targets remain unknown, hindering the rational design of Nrf2-targeted therapeutics. With this in mind, we used a combined bioinformatics and experimental approach to characterize the structure of full-length Nrf2 and its interaction with Keap1. Our results show that Nrf2 is partially disordered, with transiently structured elements in its Neh2, Neh7, and Neh1 domains. Moreover, interaction with the Kelch domain of Keap1 leads to protection of the binding motifs in the Neh2 domain of Nrf2, while the rest of the protein remains highly dynamic. This work represents the first detailed structural characterization of full-length Nrf2 and provides valuable insights into the molecular basis of Nrf2 activity modulation in oxidative stress response.

Naproxen inhibits spontaneous lung adenocarcinoma formation in KrasG12V mice

Lung cancer is the leading cause of cancer related deaths worldwide. The present study investigated the effects of naproxen (NSAID) on lung adenocarcinoma in spontaneous lung cancer mouse model. Six-week-old transgenic KrasG12V mice (n = 20; male + female) were fed modified AIN-76A diets containing naproxen (0/400 ppm) for 30 wk and euthanized at 36 wk of age. Lungs were evaluated for tumor incidence, multiplicity, and histopathological stage (adenoma and adenocarcinoma). Lung tumors were noticeable as early as 12 wk of age exclusively in the KrasG12V mice. By 36 wk age, 100% of KrasG12V mice on control diet developed lung tumors, mostly adenocarcinomas. KrasG12V mice fed control diet developed 19.8 ± 0.96 (Mean ± SEM) lung tumors (2.5 ± 0.3 adenoma, 17.3 ± 0.7 adenocarcinoma). Administration of naproxen (400 ppm) inhibited lung tumor multiplicity by ∼52% (9.4 ± 0.85; P < 0001) and adenocarcinoma by ∼64% (6.1 ± 0.6; P < 0001), compared with control-diet-fed mice. However, no significant difference was observed in the number of adenomas in either diet, suggesting that naproxen was more effective in inhibiting tumor progression to adenocarcinoma. Biomarker analysis showed significantly reduced inflammation (COX-2, IL-10), reduced tumor cell proliferation (PCNA, cyclin D1), and increased apoptosis (p21, caspase-3) in the lung tumors exposed to naproxen. Decreased serum levels of PGE2 and CXCR4 were observed in naproxen diet fed KrasG12V mice. Gene expression analysis of tumors revealed a significant increase in cytokine modulated genes (H2-Aa, H2-Ab1, Clu), which known to further modulate the cytokine signaling pathways. Overall, the results suggest a chemopreventive role of naproxen in inhibiting spontaneous lung adenocarcinoma formation in KrasG12V mice.

Ethyl acetate fraction of Spathodea campanulata (Bignoniaceae) attenuates lead acetate induced testicular toxicity in male Wistar rats.

The use of Spathodea campanulata in folklore medicine for the management of reproductive disorders has been poorly reported. We sought to investigate the protective potential of the ethyl acetate fraction of S.campanulata stem bark extract (EFSC) on lead acetate-induced (LA) testicular toxicity in male rats. Animals during a 28days treatment received dimethyl sulfoxide (DMSO, 0.1%), LA (20mg/kg), and EFSC (200mg/kg). Others received EFSC only (100, 200, and 400mg/kg) or vitamin E (100mg/kg) 1h prior to LA (20mg/kg) administration. LA administration decreased sperm counts and motility by 36.39 and 40.69% respectively in rats. Also, LA-untreated rats showed elevated malondialdehyde (MDA) and decreased total proteins in testis (260, 33%) and epididymis (62, 29%) respectively. However, EFSC (100, 200, or 400mg/kg) administrations improved sperm morphological characteristics as well as antioxidant status in LA-treated rats. EFSC (400mg/kg) showed improved testis seminiferous tubules that were almost normal in the LA-treated rats. Further, EFSC contains a high 9-octadecenoic acid methyl ester. Overall, evidence by LA-induced testicular toxicity, EFSC provides chemopreventive roles via antioxidant mechanisms.

CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects.

Simple SummaryCHEK2 germline pathogenic variants are identified at a relatively high frequency among hereditary breast cancer cases and are known to be associated with intermediate breast cancer risk i.e., 2–2.5-fold increase, compared to the general population. Histopathological characteristics and clinical outcomes of breast cancer patients who are CHEK2 carriers have not been thoroughly investigated. We have therefore sought to determine the CHEK2 variant spectrum and identify variants with possible founder effect, while investigating the clinicopathological features and outcomes of Greek patients who were CHEK2 carriers. Three variants have been identified as Greek founders. The vast majority of CHEK2-associated breast tumors were hormone receptor positive, underlying a possible benefit from chemoprophylaxis with tamoxifen. A trend for longer survival was observed in patients that underwent mastectomy and received hormone-therapy. Nearly half of patients underwent a risk-reducing surgery, which was not mandated according to current guidelines or relevant risks associated with CHEK2.CHEK2 germline pathogenic variants predispose to breast cancer and possibly to other malignancies, with their spectrum and frequency being variable among populations. Τhe majority of CHEK2-associated breast tumors are hormone receptor positive; however, relevant clinical outcomes are not well defined. Herein, we illustrate the histopathological characteristics and clinical outcomes of 52 Greek breast cancer patients who are CHEK2 carriers. Genetic analysis was performed by Sanger/massively parallel sequencing, followed by MLPA. Subsequent haplotype analysis investigated possible founder effects. Blood relatives were offered cascade testing. CHEK2 variant spectrum was characterized by variability, while influenced by founder effects. The majority of carriers, i.e., 60.8%, were diagnosed with breast cancer before the age of 45. Notably, 91.5% of breast tumors were hormone receptor positive. Hormone therapy and mastectomy at diagnosis seem to have a positive trend on overall survival, after a median follow-up of 9.5 years. Remarkably, 41.9% of patients underwent risk-reducing surgery, one third of which involved salpingo-oophorectomy. Nearly half of families responded to cascade testing. Our data highlight the need for guideline-adherent choices, based on the evidence that CHEK2 carriers are at moderate risk for breast cancer and no risk for ovarian cancer, while underscore the possible role of chemoprevention with tamoxifen.

The effects of flavonoids, green tea polyphenols and coffee on DMBA induced LINE-1 DNA hypomethylation.

The intake of carcinogenic and chemopreventive compounds are important nutritional factors related to the development of malignant tumorous diseases. Repetitive long interspersed element-1 (LINE-1) DNA methylation pattern plays a key role in both carcinogenesis and chemoprevention. In our present in vivo animal model, we examined LINE-1 DNA methylation pattern as potential biomarker in the liver, spleen and kidney of mice consuming green tea (Camellia sinensis) extract (catechins 80%), a chinese bayberry (Morella rubra) extract (myricetin 80%), a flavonoid extract (with added resveratrol) and coffee (Coffee arabica) extract. In the organs examined, carcinogen 7,12-dimethylbenz(a)anthracene (DMBA)-induced hypomethylation was prevented by all test materials except chinese bayberry extract in the kidneys. Moreover, the flavonoid extract caused significant hypermethylation in the liver compared to untreated controls and to other test materials. The tested chemopreventive substances have antioxidant, anti-inflammatory properties and regulate molecular biological signaling pathways. They increase glutathione levels, induce antioxidant enzymes, which decrease free radical damage caused by DMBA, and ultimately, they are able to increase the activity of DNA methyltransferase enzymes. Furthermore, flavonoids in the liver may inhibit the procarcinogen to carcinogen activation of DMBA through the inhibition of CYP1A1 enzyme. At the same time, paradoxically, myricetin can act as a prooxidant as a result of free radical damage, which can explain that it did not prevent hypomethylation in the kidneys. Our results demonstrated that LINE-1 DNA methylation pattern is a useful potential biomarker for detecting and monitoring carcinogenic and chemopreventive effects of dietary compounds.

How far along are we in revealing the connection between metformin and colorectal cancer?

Colorectal cancer (CRC) is among the most prevalent cancers worldwide, and its prevention and reduction of incidence is imperative. The presence of diabetes has been associated with a 30% increased risk of CRC, likely through the mechanism of hyperinsulinemia, which promotes tumorigenesis via the insulin receptor in the epithelium or by insulin-like growth factor pathways, inflammation, or adipokines, inducing cancer cell proliferation and cancer spread. Metformin, the first-line agent in treating type 2 diabetes, has a chemopreventive role in CRC development. Additionally, preclinical studies suggest synergistic effects of metformin with oxaliplatin in inhibiting in vitro models of colon cancer. Although preclinical studies on the post diagnostic use of metformin were promising and suggested its synergistic effects with chemotherapy, the data on the possible effects of metformin after surgery and other CRC treatment in the clinical setting are less conclusive, and randomized controlled trials are still lacking.

Oral nicotinamide: The role in skin cancer chemoprevention.

The incidence of skin cancer has gradually increased in the last years and exposition to ultraviolet radiation remains the main risk factor. We performed a comprehensive review on the role of nicotinamide (NAM) in the chemoprevention of skin cancers. NAM, a water-soluble form of vitamin B3, interferes with skin carcinogenesis as it regulates immunosuppressor genes such as p53 and sirtuins and restores intracellular level of NAD+, a co-enzyme essential for energy production. Efficacy and safety of NAM was evaluated in a Phase III double-blinded control-placebo study (ONTRAC), thus demonstrating that the incidence of actinic keratoses and non-melanoma skin cancers was lower in the nicotinamide group than in placebo group. Further studies showed the efficacy of NAM also in transplanted patients and among inhabitants living in arsenic contamination areas. Despite the quick response to NAM supplementation, its intake need to be carried on chronically as the efficacy seems to vanish rapidly.

Paclitaxel and Its Chemo-preventive Role in the Management of Small Lung Cancer

Based on a quantitative analysis using HPLC and UV, Alternaria alternata has been identified as a strong taxol producer. Taxol's biosynthetic efficiency has been checked using PCR detection.The development of taxol by A. alternata was investigated by inoculating the fungus on various media.The best medium for extracting the highest volume of taxol was found to be potato dextrose broth (PDB). After 21 days of incubation at 23°C with a pH of 8.5 and shaking (120 rpm) (250 g/L), the substance taxol was formed to perfection. HPLC was used to effectively purify the Alternaria alternata taxol. The taxol from Alternaria alternata displayed promising anticancer properties. The capacity of anticancer drugs to eradicate cancer cells may be used to determine their efficacy. As a result, the inhibitory effect of taxol on A549 lung adenocarcinoma cells was assessed by culturing the cells with different concentrations of the compound for 24 hours (MTT assay).

Potential Chemopreventive Role of Boldine Against Hepatocellular Carcinoma via Modulation of Cell Cycle Proteins in Rat Model.

To evaluate the chemopreventive potential of boldine against diethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC) in Wistar albino rats. Boldine is an alkaloid isolated from Peumus boldus. The primary active constituents of boldine exhibited several potential medicinal properties. The present study was evaluated to explore the chemopreventive agent of boldine on anti-proliferative efficacy against diethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC) in Wistar albino rats. The effect of boldine on cellular proliferative markers, i.e., PCNA and Ki67on hepatocellular carcinoma rats was determined by immuno expression study. Liver marker enzymes, tumor biomarker, oxidative stress markers, antioxidant status, and xenobiotic phase I and II enzymes in HCC rats were analyzed. Moreover, cell cycle proteins, i.e., p21Cip1/Kip1and p27 Cip1/Kip1, Cyclin D1, CDK 4, Cyclin E1, and CDK 2 were investigated using immuno expression analysis. Treatment of boldine protected the liver against reactive oxygen species such as hydrogen peroxide, superoxide, protein carbonyl, and lipid peroxide during hepatocarcinogenesis by boosted antioxidants-superoxide dismutase (SOD), catalase (CAT). Boldine caused a substantial enhanced detoxification process by moderating phase I and II xenobiotic-metabolizing enzymes. Besides, the study found that boldine significantly inhibited the cellular proliferative markers like PCNA and Ki67 and regulated the specific cell cycle-associated proteins by up-regulated expression of p21Cip1/Kip1and p27 Cip1/Kip1 and down-regulated expression of Cyclin D1, CDK 4, Cyclin E1, and CDK 2. Our data manifests the anti-proliferative effect of boldine, which negatively modulates cellular proliferation and regulates cell cycle by protecting the cell from reactive oxygen species (ROS), suggesting that boldine establishes it as a chemopreventive agent in diethylnitrosamine-induced hepatocarcinogenesis in rats.

Dietary phytochemicals and their role in cancer chemoprevention.

Journal of Cancer Metastasis and Treatment is an open access journal, focusing on basic and clinical studies related to cancer cell, cell biology, oncology, radiation therapy and radiology, obstetrics and gynecology, pediatrics, surgery, hematology, neuro-oncology, etc.

Chemoprevention of breast cancer; toward better outcomes

Breast cancer is one of the major burdens that affect women and their life. Many studies showed that many chemopreventive agents have anticancer effect; however, some studies were contrary to them. This article reviewed and summarized the available medical evidences of chemoprevention in breast cancer. An extensive literature search was carried out in the following databases including: Medline (PubMed interface), Scopus, and Google Scholar to identify articles that discussed the role of chemoprevention in breast cancer. The following keywords were used independently and in combination including carcinogenesis, breast cancer, and chemoprevention in the search process. The retrieved articles were further explored in order to find other relevant resources. Although various chemopreventive agents have been investigated in breast cancer and there have been major achievements in this field, more research work and clinical trials are needed to determine the therapeutic efficiencies of these agents in human being.

6]-Gingerol impedes 7,12-dimethylbenz(a)anthracene-induced inflammation and cell proliferation-associated hamster buccal pouch carcinogenesis through modulating Nrf2 signaling events.

The present study examines the chemopreventive role of [6]-gingerol, an active component of ginger, on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis models. The HBP has been developed with an addition of 0.5% of DMBA to the HBP area three times per week, up to the end of the 16th experimental week. At the end of the experiment, we noticed 100% tumor incidence and precancerous lesions, such as dysplasia, hyperplasia, keratosis, and well-differentiated squamous cell carcinoma, in DMBA-induced HBP. Furthermore, we observed that [6]-gingerol inhibited the increased thiobarbituric acid-reactive substancesand decreased antioxidant levels in DMBA-induced hamsters. Moreover, [6]-gingerol inhibits DMBA-exposed over expression of inflammatory markers (inducible nitric oxide synthase, interleukin [IL]-1β, IL-6, cyclooxygenase-2, and tumor necrosis factor-α) and cell proliferation markers (cyclin D1, proliferating cell nuclear antigen); induces proapoptotic markers in HBP. Nuclear factor erythroid-2-related factor-2 (Nrf2) is a major antioxidant transcription factor, which regulates the antioxidant gene-dependent scavenge of tumor proliferation and apoptosis. Overexpression of Nrf2 signaling plays a pivotal role and can be a novel target in preventing carcinogenesis. In this study, [6]-gingerol restores the DMBA-induced depletion of Nrf2 signaling and thereby prevents buccal pouch carcinogenesis in hamsters. These results point out that [6]-gingerol impedes the responses of inflammatory and cell proliferation-associated progression of cancer through the action of Nrf2 signaling.

Chemopreventive Role of Apigenin against the Synergistic Carcinogenesis of Human Papillomavirus and 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone.

Tobacco smoke and human papillomavirus (HPV) are both crucial causes of cancer, and their cooperative carcinogenesis has drawn more attention in recent years. Apigenin (AP), a typical flavonoid abundantly found in flowers of plants, vegetables, and fruits, has been demonstrated to exert an anti-carcinogenic effect on various types of cancer. In this study, we investigated the capability of AP against malignant transformation and DNA damage of immortalized human esophageal epithelial (SHEE) cells induced by the synergism of HPV18 and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The results indicated that the enhancement of migration, invasion, and proliferation ability of SHEE cells induced by HPV and NNK could be effectively inhibited by AP. Moreover, the levels of pyridyloxybutylated (POB)-DNA adducts induced by NNK via P450-catalyzed metabolic activation could also be significantly suppressed by AP. Further analyses on the molecular mechanism revealed that AP inhibited the synergistic carcinogenesis of NNK and HPV on SHEE cells by reducing the expression of mutp53, CDK4, Cyclin D1, and p-Rb (Ser 780), increasing caspase-3 activity, thereby arresting the cell cycle at G1 phase and promoting apoptosis of SHEE cells. We hypothesize that the decrease in NNK-induced POB-DNA adduct levels is related to the deactivation of P450 by AP, which needs to be confirmed in future studies. This study highlights that AP may be employed as a promising chemopreventive agent against cancers in smokers with an HPV infection.

Specialist recommendation for chemoprevention medications in patients at familial risk of breast cancer: a cross-sectional survey in England

In England, the National Institute for Health and Care Excellence guideline for familial breast cancer recommends chemoprevention for women at high and moderate familial risk of breast cancer. However, prescribing of chemoprevention has not improved since the introduction of the guideline in 2013. The study aims to identify the current practice, in England, of familial cancer specialists offering chemoprevention and recommending prescribing in primary care. This was an anonymized national cross-sectional survey of familial breast cancer risk services in England. Lead clinicians were sent an online survey link. The survey questions included whether chemoprevention was offered/considered for high- and moderate-risk women, when chemoprevention prescribing and recommendation to primary care started, medications prescribed, age groups considered for chemoprevention, and existence of a shared prescribing protocol with primary care. The survey was sent to 115 hospital services; responses from 50 services (43%) were included in the analysis. Of the 40 services offering chemoprevention for high-risk women, 15 (38%) did not prescribe but 31 (78%) recommended prescribing to primary care. Of the 31 services considering chemoprevention for moderate risk, eight (26%) did not prescribe with 26 (84%) recommended prescribing to primary care. Only three services reported having a shared protocol with primary care. Within 3 years of the guidelines, many services recognized the role of chemoprevention for both high and moderate risk with a key role for primary care to initiate prescribing. However, there is still room for improvement.

Realizing the Potential of Blueberry as Natural Inhibitor of Metastasis and Powerful Apoptosis Inducer: Tapping the Treasure Trove for Effective Regulation of Cell Signaling Pathways

Blueberries belong to the genus Vaccinium of the family Ericaceae. Rapidly accumulating experimentally verified data is uncovering the tremendous pharmacological properties of biologically active constituents of blueberries against different diseases. Our rapidly evolving knowledge about the multifaceted nature of cancer has opened new horizons to search for different strategies to target multiple effectors of oncogenic networks to effectively inhibit cancer onset and progression. Excitingly, whole blueberry powder and various bioactive constituents (pterostilbene, malvidin-3-galactoside) of blueberries have been shown to efficiently inhibit metastasis in animal models. These results are encouraging and future studies must focus on the identification of cell signaling pathways effectively modulated by blueberries in different cancers. It seems exciting to note that researchers are focusing on metastasis inhibitory effects of blueberry; however, to reap full benefits, it is necessary to take a step back and critically re-interpret the mechanisms used by active components of blueberry to inhibit or prevent metastasis. JAK/STAT, TGF/SMAD, Notch, SHH/GLI, and Wnt/ β-Catenin have been shown to be directly involved in the regulation of metastasis. However, because of limited studies, it is difficult to critically assess the true potential of blueberry. Loss of apoptosis, metastasis and deregulation of signaling pathways are branching trajectories of molecular oncology. Accordingly, we have to emphasize on these essential facets to realistically claim blueberry as "Superfood". Different clinical trials have been conducted to gather clinical evidence about the chemopreventive role of blueberry or its bioactive components in cancer patients. But it seems clear that because of the lack of sufficient proof-of-concept studies, we cannot extract significant information about the transition of blueberry into the next phases of clinical trials. Overview of the existing scientific evidence revealed visible knowledge gaps and a better understanding of the targets of blueberry will be helpful in efficient and meaningful translation of laboratory findings to clinically effective therapeutics.

Anti-neoplastic Potential of Flavonoids and Polysaccharide Phytochemicals in Glioblastoma.

Clinically, gliomas are classified into four grades, with grade IV glioblastoma multiforme being the most malignant and deadly, which accounts for 50% of all gliomas. Characteristically, glioblastoma involves the aggressive proliferation of cells and invasion of normal brain tissue, outcomes as poor patient prognosis. With the current standard therapy of glioblastoma; surgical resection and radiotherapy followed by adjuvant chemotherapy with temozolomide, it remains fatal, because of the development of drug resistance, tumor recurrence, and metastasis. Therefore, the need for the effective therapeutic option for glioblastoma remains elusive. Previous studies have demonstrated the chemopreventive role of naturally occurring pharmacological agents through preventing or reversing the initiation phase of carcinogenesis or arresting the cancer progression phase. In this review, we discuss the role of natural phytochemicals in the amelioration of glioblastoma, with the aim to improve therapeutic outcomes, and minimize the adverse side effects to improve patient’s prognosis and enhancing their quality of life.

Regulation of Nrf2/ARE Pathway by Dietary Flavonoids: A Friend or Foe for Cancer Management?

The nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is an important cell signaling mechanism in maintaining redox homeostasis in humans. The role of dietary flavonoids in activating Nrf2/ARE in relation to cancer chemoprevention or cancer promotion is not well established. Here we summarize the dual effects of flavonoids in cancer chemoprevention and cancer promotion with respect to the regulation of the Nrf2/ARE pathway, while underlying the possible cellular mechanisms. Luteolin, apigenin, quercetin, myricetin, rutin, naringenin, epicatechin, and genistein activate the Nrf2/ARE pathway in both normal and cancer cells. The hormetic effect of flavonoids has been observed due to their antioxidant or prooxidant activity, depending on the concentrations. Reported in vitro and in vivo investigations suggest that the activation of the Nrf2/ARE pathway by either endogenous or exogenous stimuli under normal physiological conditions contributes to redox homeostasis, which may provide a mechanism for cancer chemoprevention. However, some flavonoids, such as luteolin, apigenin, myricetin, quercetin, naringenin, epicatechin, genistein, and daidzein, at low concentrations (1.5 to 20 µM) facilitate cancer cell growth and proliferation in vitro. Paradoxically, some flavonoids, including luteolin, apigenin, and chrysin, inhibit the Nrf2/ARE pathway in vitro. Therefore, even though flavonoids play a major role in cancer chemoprevention, due to their possible inducement of cancer cell growth, the effects of dietary flavonoids on cancer pathophysiology in patients or appropriate experimental animal models should be investigated systematically.

Inhibition of the Activity of Cyclophilin A Impedes Prolactin Receptor-Mediated Signaling, Mammary Tumorigenesis, and Metastases

SummaryProlactin (PRL) and its receptor (PRLr) play important roles in the pathogenesis of breast cancer. Cyclophilin A (CypA) is a cis-trans peptidyl-prolyl isomerase (PPI) that is constitutively associated with the PRLr and facilitates the activation of the tyrosine kinase Jak2. Treatment with the non-immunosuppressive prolyl isomerase inhibitor NIM811 or CypA short hairpin RNA inhibited PRL-stimulated signaling, breast cancer cell growth, and migration. Transcriptomic analysis revealed that NIM811 inhibited two-thirds of the top 50 PRL-induced genes and a reduction in gene pathways associated with cancer cell signaling. In vivo treatment of NIM811 in a TNBC xenograft lessened primary tumor growth and induced central tumor necrosis. Deletion of CypA in the MMTV-PyMT mouse model demonstrated inhibition of tumorigenesis with significant reduction in lung and lymph node metastasis. The regulation of PRLr/Jak2-mediated biology by NIM811 demonstrates that a non-immunosuppressive prolyl isomerase inhibitor can function as a potential breast cancer therapeutic.

The suggested chemopreventive association of metformin with prostate cancer in diabetic patients

PurposeMetformin, an insulin sensitizer, is the most common first-line antidiabetic therapy. There is increasing evidence suggesting metformin can prevent the emergence of prostate cancer (CaP). We aimed to analyze the chemopreventive role of metformin, in conjunction with other putative chemopreventive medications (statins, proton-pump-inhibitors, alpha-blockers, 5-alpha-reductase inhibitors, diabetic medications) in a population-based cohort study. MethodsData were incorporated from the Institute for Clinical and Evaluative Sciences to identify all diabetic men aged 66 and above with prior history of a negative prostate biopsy (PB) between 1994 and 2016, who were not on any of the medications prior to study inclusion. Multivariable Cox regression models with time-dependent covariates were used to assess the association of metformin to CaP diagnosis, subsequent PB, and use of androgen deprivation therapy (ADT). All models were adjusted for age, rurality, comorbidity, and year of study inclusion. ResultsOverall, 2,332 diabetic men were included, with a median follow-up time of 9.4 years (interquartile range 5.4–13.4 years). A total of 2,036 patients (87.3%) received metformin. Compared to non-metformin users, metformin use was associated with decreased CaP diagnosis rate (HR 0.69, 95%CI 0.54–0.88, P = 0.003), lower hazard of undergoing an additional PB (HR 0.64, 95%CI 0.44–0.95, P = 0.03), and receiving ADT (HR 0.72, 95%CI 0.54–0.96, P = 0.003). ConclusionMen receiving metformin were less likely to have suspected or diagnosed CaP, and in those with CaP, the use of ADT was less common. Ongoing prospective randomized studies will determine if these findings correspond to the suggested associations of metformin in the emergence and/or progression of CaP.

Discovery of Harmaline as a Potent Inhibitor of Sphingosine Kinase-1: A Chemopreventive Role in Lung Cancer.

The sphingosine kinase-1/sphingosine-1-phosphate pathway is linked with the cancer progression and survival of the chemotherapy-challenged cells. Sphingosine kinase-1 (SphK1) has emerged as an attractive drug target, but their inhibitors from natural sources are limited. In this study, we have chosen harmaline, one of the β-carboline alkaloids, and report its mechanism of binding to SphK1 and subsequent inhibition. Molecular docking combined with fluorescence binding studies revealed that harmaline binds to the substrate-binding pocket of SphK1 with an appreciable binding affinity and significantly inhibits the kinase activity of SphK1 with an IC50 value in the micromolar range. The cytotoxic effect of harmaline on non-small-cell lung cancer cells by MTT assay was found to be higher for H1299 compared to A549. Harmaline induces apoptosis in non-small-cell lung carcinoma cells (H1299 and A549), possibly via the intrinsic pathway. Our findings suggest that harmaline could be implicated as a scaffold for designing potent anticancer molecules with SphK1 inhibitory potential.