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Hasan Mukhtar

Publications and source records attributed to Hasan Mukhtar.

At least 37 records · Page 2Linked to original sources
PubMed2005

Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer.

Prostate cancer is the most common invasive malignancy and the second leading cause of cancer-related deaths among U.S. males, with a similar trend in many Western countries. One approach to control this malignancy is its prevention through the use of agents present in diet consumed by humans. Pomegranate from the tree Punica granatum possesses strong antioxidant and antiinflammatory properties. We recently showed that pomegranate fruit extract (PFE) possesses remarkable antitumor-promoting effects in mouse skin. In this study, employing human prostate cancer cells, we evaluated the antiproliferative and proapoptotic properties of PFE. PFE (10-100 microg/ml; 48 h) treatment of highly aggressive human prostate cancer PC3 cells resulted in a dose-dependent inhibition of cell growth/cell viability and induction of apoptosis. Immunoblot analysis revealed that PFE treatment of PC3 cells resulted in (i) induction of Bax and Bak (proapoptotic); (ii) down-regulation of Bcl-X(L) and Bcl-2 (antiapoptotic); (iii) induction of WAF1/p21 and KIP1/p27; (iv) a decrease in cyclins D1, D2, and E; and (v) a decrease in cyclin-dependent kinase (cdk) 2, cdk4, and cdk6 expression. These data establish the involvement of the cyclin kinase inhibitor-cyclin-cdk network during the antiproliferative effects of PFE. Oral administration of PFE (0.1% and 0.2%, wt/vol) to athymic nude mice implanted with androgen-sensitive CWR22Rnu1 cells resulted in a significant inhibition in tumor growth concomitant with a significant decrease in serum prostate-specific antigen levels. We suggest that pomegranate juice may have cancer-chemopreventive as well as cancer-chemotherapeutic effects against prostate cancer in humans.

Animals↗
PubMed2005

Lupeol, a fruit and vegetable based triterpene, induces apoptotic death of human pancreatic adenocarcinoma cells via inhibition of Ras signaling pathway.

Pancreatic cancer is an exceptionally aggressive disease, the treatment of which has largely been unsuccessful due to higher resistance offered by pancreatic cancer cells to conventional approaches such as surgery, radiation and/or chemotherapy. The aberration of Ras oncoprotein has been linked to the induction of multiple signaling pathways and to the resistance offered by pancreatic cancer cells to apoptosis. Therefore, there is a need for development of new and effective chemotherapeutic agents which can target multiple pathways to induce responsiveness of pancreatic cancer cells to death signals. In this study, human pancreatic adenocarcinoma cells AsPC-1 were used to investigate the effect of Lupeol on cell growth and its effects on the modulation of multiple Ras-induced signaling pathways. Lupeol caused a dose-dependent inhibition of cell growth as assessed by MTT assay and induction of apoptosis as assessed by flow cytometry, fluorescence microscopy and western blotting. Lupeol treatment to cells was found to significantly reduce the expression of Ras oncoprotein and modulate the protein expression of various signaling molecules involved in PKCalpha/ODC, PI3K/Akt and MAPKs pathways along with a significant reduction in the activation of NFkappaB signaling pathway. Our data suggest that Lupeol can adopt a multi-prong strategy to target multiple signaling pathways leading to induction of apoptosis and inhibition of growth of pancreatic cancer cells. Lupeol could be a potential agent against pancreatic cancer, however, further in-depth in vivo studies are warranted.

Adenocarcinoma↗
PubMed2005

Anti-proliferative and proapoptotic effects of (-)-epigallocatechin-3-gallate on human melanoma: possible implications for the chemoprevention of melanoma.

Melanoma accounts for only about 4% of all skin cancer cases but most of skin cancer-related deaths. Standard systemic therapies such as interferon (IFN) have not been adequately effective in the management of melanoma. Therefore, novel approaches are needed for prevention and treatment of this disease. Chemoprevention by naturally occurring agents present in food and beverages has shown benefits in certain cancers including nonmelanoma skin cancers. Here, employing 2 human melanoma cell lines (A-375 amelanotic malignant melanoma and Hs-294T metastatic melanoma) and normal human epidermal melanocytes (NHEM), we studied the antiproliferative effects of epigallocatechin-3-gallate (EGCG), the major polyphenolic antioxidant present in green tea. EGCG treatment was found to result in a dose-dependent decrease in the viability and growth of both melanoma cell lines. Interestingly, at similar EGCG concentrations, the normal melanocytes were not affected. EGCG treatment of the melanoma cell lines resulted in decreased cell proliferation (as assessed by Ki-67 and PCNA protein levels) and induction of apoptosis (as assessed cleavage of PARP, TUNEL assay and JC-1 assay). EGCG also significantly inhibited the colony formation ability of the melanoma cells studied. EGCG treatment of melanoma cells resulted in a downmodulation of anti-apoptotic protein Bcl2, upregulation of proapoptotic Bax and activation of caspases -3, -7 and -9. Furthermore, our data demonstrated that EGCG treatment resulted in a significant, dose-dependent decrease in cyclin D1 and cdk2 protein levels and induction of cyclin kinase inhibitors (ckis) p16INK4a, p21WAF1/CIP1 and p27KIP1. Our data suggest that EGCG causes significant induction of cell cycle arrest and apoptosis of melanoma cells that is mediated via modulations in the cki-cyclin-cdk network and Bcl2 family proteins. Thus, EGCG, alone or in conjunction with current therapies, could be useful for the management of melanoma.

Agar↗
PubMed2005

Ablation of either p21 or Bax prevents p53-dependent apoptosis induced by green tea polyphenol epigallocatechin-3-gallate.

Treatment with epigallocatechin-3-gallate (EGCG), a polyphenolic compound of green tea, results in activation of p53 and induction of apoptosis in prostate cancer LnCaP cells. However, no direct evidence has delineated the role of p53 and p53-dependent pathways in EGCG-mediated apoptosis. To understand the mechanism of negative growth regulation of prostate cancer cells by EGCG we undertook a genetic approach and generated an isogenic pair of prostate carcinoma cells PC3 (p53-/-) by stably introducing a cDNA encoding wild-type p53. Treatment of the resultant cells, PC3-p53, with EGCG led to, as reported earlier in LnCaP cells, an increase in p53 protein, which exacerbated both G1 arrest and apoptosis. This response was accompanied by an increase in the levels of p21 and Bax. The cells lacking p53 continued to cycle and did not undergo apoptosis upon treatment with similar concentrations of EGCG, thus establishing the action of EGCG in a p53-dependent manner. This observation was revalidated in another prostate cancer LNCaP cells harboring wild-type p53. Inactivation of p53 using small interfering RNA (siRNA) rendered these cells resistant to EGCG-mediated apoptosis. Because p53 activation led to increase in p21 and Bax, we investigated whether these two proteins are important in this process. Ablation of p21 protein by siRNA prevented G1 arrest and apoptosis in PC3-p53 cells. The p53-dependent increase in Bax expression altered the Bax/Bcl-2 ratio and paralleled the activation of caspase 9 and 3 and cleavage of PARP. Transfection of cells with Bax siRNA abolished these effects and inhibited apoptosis but did not affect the accumulation of the cells in G1. In summary, using isogenic cell lines and siRNA, we have clearly demonstrated that EGCG activates growth arrest and apoptosis primarily via p53-dependent pathway that involves the function of both p21 and Bax such that down-regulation of either molecule confers a growth advantage to the cells.

Apoptosis↗
PubMed2005

Cannabinoid receptor as a novel target for the treatment of prostate cancer.

Cannabinoids, the active components of Cannabis sativa Linnaeus (marijuana) and their derivatives have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory effects and tumor regression. Here we show that expression levels of both cannabinoid receptors, CB1 and CB2, are significantly higher in CA-human papillomavirus-10 (virally transformed cells derived from adenocarcinoma of human prostate tissue), and other human prostate cells LNCaP, DUI45, PC3, and CWR22Rnu1 than in human prostate epithelial and PZ-HPV-7 (virally transformed cells derived from normal human prostate tissue) cells. WIN-55,212-2 (mixed CB1/CB2 agonist) treatment with androgen-responsive LNCaP cells resulted in a dose- (1-10 micromol/L) and time-dependent (24-48 hours) inhibition of cell growth, blocking of CB1 and CB2 receptors by their antagonists SR141716 (CB1) and SR144528 (CB2) significantly prevented this effect. Extending this observation, we found that WIN-55,212-2 treatment with LNCaP resulted in a dose- (1-10 micromol/L) and time-dependent (24-72 hours) induction of apoptosis (a), decrease in protein and mRNA expression of androgen receptor (b), decrease in intracellular protein and mRNA expression of prostate-specific antigen (c), decrease in secreted prostate-specific antigen levels (d), and decrease in protein expression of proliferation cell nuclear antigen and vascular endothelial growth factor (e). Our results suggest that WIN-55,212-2 or other non-habit-forming cannabinoid receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer.

Adenocarcinoma↗
PubMed2005

Green tea constituent epigallocatechin-3-gallate selectively inhibits COX-2 without affecting COX-1 expression in human prostate carcinoma cells.

Overexpression of cyclooxygenase (COX)-2 has been implicated in many pathologic conditions, including cancer. One practical inference of this finding is that sustained inhibition of COX-2 could serve as a promising target for prevention or therapy of cancer. Conventional nonsteroidal antiinflammatory drugs (NSAIDs) and recently developed COX-2-specific inhibitors have shown considerable promise in prevention of some forms of human cancer; however, its application is limited due to severe toxic side effects on normal cells. Therefore, there is a need to define novel, nontoxic dietary constituents with proven chemopreventive effects through other pathways that also possess COX-2 but not COX-1 inhibitory activity. Recent studies on green tea and its major polyphenolic constituent (-)epigallocatechin-3-gallate (EGCG) have established its remarkable cancer preventive and some cancer therapeutic effects. Here, we show that EGCG inhibits COX-2 without affecting COX-1 expression at both the mRNA and protein levels, in androgen-sensitive LNCaP and androgen-insensitive PC-3 human prostate carcinoma cells. Based on our study, it is tempting to suggest that a combination of EGCG with chemotherapeutic drugs could be an improved strategy for prevention and treatment of prostate cancer.

Antineoplastic Agents↗
PubMed2005

Photochemoprevention of ultraviolet B signaling and photocarcinogenesis.

Exposure to solar radiation, particularly its ultraviolet (UV) B component, has a variety of harmful effects on human health. Some of these effects include sunburn cell formation, basal and squamous cell cancers, melanoma, cataracts, photoaging of the skin, and immune suppression. Amongst these various adverse effects of UV radiation, skin cancer is of the greatest concern. Over the years, changes in lifestyle has led to a significant increase in the amount of UV radiation that people receive, and this consequently has led to a surge in the incidence of skin cancer. The development of skin cancer is a complex multistage phenomenon involving three distinct stages exemplified by initiation, promotion and progression stages. Each of these stages is mediated via alterations in various cellular, biochemical, and molecular changes. Initiation, the first step in the carcinogenesis process is essentially an irreversible step in which genetic alterations occur in genes that ultimately leads to DNA modification and fixation of mutation. Tumor promotion is the essential process in cancer development involving clonal expansion of initiated cells giving rise to pre-malignant and then to malignant lesions, essentially by alterations in signal transduction pathways. Tumor progression involves the conversion of pre-malignant and malignant lesions into an invasive and potentially metastatic malignant tumor. All these processes for skin cancer development involve stimulation of DNA synthesis, DNA damage and proliferation, inflammation, immunosuppression, epidermal hyperplasia, cell cycle dysregulation, depletion of antioxidant defenses, impairment of signal transduction pathways, induction of cyclooxygenase, increase in prostaglandin synthesis, and induction of ornithine decarboxylase. Photochemoprevention has been appreciated as a viable approach to reduce the occurrence of skin cancer and in recent years, the use of agents, especially botanical antioxidants, present in the common diet and beverages consumed by human population have gained considerable attention as photochemopreventive agents for human use. Many such agents have also found a place in skin care products. Although this is more common in oriental countries, its popularity is significantly growing in western countries. In this article, we have summarized the available information of laboratory studies on UVB-mediated signaling that can be exploited as targets for photochemoprevention. We suggest that the use of skin care products supplemented with proven chemopreventive agents in conjunction with the use of sunscreens along with educational efforts may be an effective strategy for reducing UV-induced photodamage and skin cancer in humans. The mechanistic basis for the use of such products is discussed.

Chemoprevention↗
PubMed2005

Anthocyanin- and hydrolyzable tannin-rich pomegranate fruit extract modulates MAPK and NF-kappaB pathways and inhibits skin tumorigenesis in CD-1 mice.

Chemoprevention has come of age as an effective cancer control modality; however, the search for novel agent(s) for the armamentarium of cancer chemoprevention continues. We argue that agents capable of intervening at more than one critical pathway in the carcinogenesis process will have greater advantage over other single-target agents. Pomegranate fruit extract (PFE) derived from the tree Punica granatum possesses strong antioxidant and antiinflammatory properties. Pomegranate fruit was extracted with acetone and analyzed based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and found to contain anthocyanins, ellagitannins and hydrolyzable tannins. We evaluated whether PFE possesses antitumor-promoting effects. We first determined the effect of topical application of PFE to CD-1 mice against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced conventional markers and other novel markers of skin tumor promotion. We found that topical application of PFE (2 mg/mouse) 30 min prior to TPA (3.2 nmole/mouse) application on mouse skin afforded significant inhibition, in a time-dependent manner, against TPA-mediated increase in skin edema and hyperplasia, epidermal ornithine decarboxylase (ODC) activity and protein expression of ODC and cyclooxygenase-2. We also found that topical application of PFE resulted in inhibition of TPA-induced phosphorylation of ERK1/2, p38 and JNK1/2, as well as activation of NF-kappaB and IKKalpha and phosphorylation and degradation of IkappaBalpha. We next assessed the effect of skin application of PFE on TPA-induced skin tumor promotion in 7,12-dimethylbenz(a)anthracene-initiated CD-1 mouse. The animals pretreated with PFE showed substantially reduced tumor incidence and lower tumor body burden when assessed as total number of tumors per group, percent of mice with tumors and number of tumors per animal as compared to animals that did not receive PFE. In TPA-treated group, 100% of the mice developed tumors at 16 weeks on test, whereas at this time in PFE-treated group, only 30% mice exhibited tumors. Skin application of PFE prior to TPA application also resulted in a significant delay in latency period from 9 to 14 weeks and afforded protection when tumor data were considered in terms of tumor incidence and tumor multiplicity. The results of our study provide clear evidence that PFE possesses antiskin-tumor-promoting effects in CD-1 mouse. Because PFE is capable of inhibiting conventional as well as novel biomarkers of TPA-induced tumor promotion, it may possess chemopreventive activity in a wide range of tumor models. Thus, an in-depth study to define active agent(s) in PFE capable of affording antitumor-promoting effect is warranted.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2005

Prognostic significance of metastasis-associated protein S100A4 (Mts1) in prostate cancer progression and chemoprevention regimens in an autochthonous mouse model.

PURPOSE: We recently showed that metastasis-promoting Mts1 gene (S100A4) and protein is overexpressed during progression of prostate cancer in humans. The purpose of this study was to assess the expression of S100A4 during autochthonous prostate cancer progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Because oral consumption of green tea polyphenols (GTP) has been shown to inhibit metastasis and prostate cancer in TRAMP, we further assessed the significance of S100A4 during chemoprevention regimen. EXPERIMENTAL DESIGN: Male TRAMP mice 8 weeks of age were equally divided into two groups. A freshly prepared 0.1% GTP solution in tap water was supplied thrice a week to experimental animals as the sole source of drinking fluid for 24 weeks, whereas the control group of animals received the same tap water throughout the experiment. The animals were sacrificed at 0, 8, 16, and 24 weeks of GTP feeding and were analyzed for S100A4 and E-cadherin. Additional untreated and treated nontransgenic controls were also included in the study. RESULTS: With the progression of age and prostate cancer growth in TRAMP mice, an increase in the expression of S100A4 at mRNA and protein level in dorsolateral prostate, but not in nontransgenic mice, occurred. GTP feeding to TRAMP mice resulted in marked inhibition of prostate cancer progression, which was associated with reduction of S100A4 and restoration of E-cadherin. CONCLUSIONS: S100A4 represents a promising marker for prostate cancer progression and could be employed as a biomarker in chemoprevention regimens.

Administration, Oral↗
PubMed2005

Induction of apoptosis by Panduratin A isolated from Kaempferia pandurata in human colon cancer HT-29 cells.

We previously showed that panduratin A isolated from an extract of Kaempferia pandurata (Zingiberaceae) was a strong inhibitor of cyclooxygenase-2 (COX-2) in RAW264.7 cells, suggesting a potential use of panduratin A as an anti-inflammatory agent. In the present study, we have investigated the effects of panduratin A on cytoplasmic levels of COX-2, as well as proliferation and apoptosis in human colon cancer cells HT-29. Cell proliferation and induction of apoptosis was determined by the MTT assay, DNA fragmentation measurement, flow cytometric analysis, nuclear staining and Western blotting. The MTT assay indicated that panduratin A exhibited cytotoxicity with an IC50 value of 28 microM. The cytotoxic effects of panduratin A were found to be accompanied by the dose-dependent induction of apoptosis as assessed by DNA fragmentation and apoptotic bodies. In addition, treatment with an apoptosis-inducing concentration of panduratin A resulted in cleavage of poly(ADP-ribose) polymerase (PARP) with a concomitant decrease in procaspase-3 protein. Our study provides evidence for cell growth inhibition and induction of apoptosis by panduratin A in human colon cancer cells, suggesting its potential use as a cancer chemopreventive and therapeutic agent.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Oral consumption of green tea polyphenols inhibits insulin-like growth factor-I-induced signaling in an autochthonous mouse model of prostate cancer.

We earlier demonstrated that oral infusion of green tea polyphenols inhibits development and progression of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Evidence indicates that elevated levels of IGF-I with concomitant lowering of IGF binding protein (IGFBP)-3 are associated with increased risk for prostate cancer development and progression. In this study, we examined the role of IGF/IGFBP-3 signaling and its downstream and other associated events during chemoprevention of prostate cancer by green tea polyphenols in TRAMP mice. Our data demonstrated an increase in the levels of IGF-I, phosphatidylinositol 3'-kinase, phosphorylated Akt (Thr-308), and extracellular signal-regulated kinase 1/2 with concomitant decrease in IGFBP-3 in dorso-lateral prostate of TRAMP mice during the course of cancer progression, i.e., as a function of age. Continuous green tea polyphenol infusion for 24 weeks to these mice resulted in substantial reduction in the levels of IGF-I and significant increase in the levels of IGFBP-3 in the dorso-lateral prostate. This modulation of IGF/IGFBP-3 was found to be associated with an inhibition of protein expression of phosphatidylinositol 3'-kinase, phosphorylated forms of Akt (Thr-308) and extracellular signal-regulated kinase 1/2. Furthermore, green tea polyphenol infusion resulted in marked inhibition of markers of angiogenesis and metastasis most notably vascular endothelial growth factor, urokinase plasminogen activator, and matrix metalloproteinases 2 and 9. Based on our data, we suggest that IGF-I/IGFBP-3 signaling pathway is a prime pathway for green tea polyphenol-mediated inhibition of prostate cancer that limits the progression of cancer through inhibition of angiogenesis and metastasis.

Adenocarcinoma↗
PubMed2004

Lupeol modulates NF-kappaB and PI3K/Akt pathways and inhibits skin cancer in CD-1 mice.

Chemoprevention has become an effective cancer control modality; however, the search for novel agent(s) for the armamentarium of cancer chemoprevention continues. We argue that agents capable for inhibition of promotion stage of tumorigenesis with the ability to intervene at several critical pathways in the tumorigenesis process will have greater advantage over other single-target agents. Lupeol, a triterpene, is the principal constituent of common fruit plants such as olive, mango, fig and medicinal herbs that have been used to treat skin aliments. Lupeol has been reported to possess a wide range of medicinal properties that include strong antioxidant, antimutagenic, anti-inflammatory and antiarthritic effects. In the present study, we show that Lupeol possesses antitumor-promoting effects in a mouse skin tumorigenesis model. We first determined the effect of topical application of Lupeol to CD-1 mouse against 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced conventional markers and other novel markers of skin tumor promotion. We found that topical application of Lupeol (1-2 mg/mouse) 30 min prior to TPA (3.2 nmol/mouse) application onto the skin of CD-1 mice afforded significant inhibition, in a time- and dose-dependent manner, against TPA-mediated increase in (i) skin edema and hyperplasia, (ii) epidermal ornithine decarboxylase (ODC) activity, and (iii) protein expression of ODC, cyclo-oxygenase-2 and nitric oxide synthase. As of the role of nuclear factor kappa B (NF-kappaB) and phosphatidyl inositol 3-kinase (PI3K)/Akt signaling in tumor promotion, we next determined the effect of topical application of Lupeol to mouse skin against these signaling pathways. We found that Lupeol treatment to mouse skin resulted in the inhibition of TPA-induced (i) activation of PI3K, (ii) phosphorylation of Akt at Thr(308), (iii) activation of NF-kappaB and IKKalpha, and (iv) degradation and phosphorylation of IkappaBalpha. The animals pretreated with Lupeol showed significantly reduced tumor incidence, lower tumor body burden and a significant delay in the latency period for tumor appearance. At the termination of the experiment at 28 weeks, 100% of the animals in TPA-treated group exhibited seven to eight tumors/mouse, whereas only 53% of the mice receiving Lupeol prior to TPA treatment exhibited one to three tumors/mouse. These results for the first time provide evidence that Lupeol possesses antiskin tumor-promoting effects in CD-1 mouse and inhibits conventional as well as novel biomarkers of tumor promotion. We suggest that Lupeol is an attractive antitumor-promoting agent that must be evaluated in tumor models other than skin carcinogenesis.

Administration, Topical↗
PubMed2004

Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model.

Epidemiological studies and clinical observations suggest that nonsteroidal anti-inflammatory drugs and certain selective cyclooxygenase (COX)-2 inhibitors may reduce the relative risk of clinically evident prostate cancer. This prompted us to investigate the chemopreventive potential of celecoxib, a selective COX-2 inhibitor, against prostate carcinogenesis in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Similar to prostate cancer in humans, prostate malignancies in TRAMP mice progress from precursor intraepithelial lesions, to invasive carcinoma that metastasizes to lymph nodes, liver, lungs, and occasionally to bone. The basal enzyme activity and protein expression of COX-2 is significantly higher (>4-fold) in the dorsolateral prostate of TRAMP mice up to 24 weeks of age compared with their nontransgenic littermates. Eight-week-old TRAMP mice were randomly divided and fed either control diet (AIN 76A) or a custom prepared AIN 76A diet containing 1500-ppm celecoxib ad libitum for 24 weeks, a dosage that would compare with the normal recommended dose for the treatment of human disease. Studies from two independent experiments, each consisting of 10 mice on test, showed that the cumulative incidence of prostate cancer development at 32 weeks of age in animals fed with AIN 76A diet was 100% (20 of 20) as observed by tumor palpation, whereas 65% (13 of 20), 35% (7 of 20), and 20% (4 of 20) of the animals exhibited distant site metastases to lymph nodes, lungs, and liver. Celecoxib supplementation to TRAMP mice from 8-32 weeks of age exhibited significant reduction in tumor development (5 of 20) with no signs of metastasis. Celecoxib feeding resulted in a significant decrease in prostate (56%; P < 0.0003) and genitourinary weight (48%; P < 0.008). Sequential magnetic resonance imaging analysis of celecoxib-fed mice documented lower prostate volume compared with the AIN 76A-fed group. Histopathological examination of celecoxib-fed animals showed reduced proliferation, and down-modulation of COX-2 and prostaglandin E2 levels in the dorsolateral prostate and plasma, respectively. These results correlated with retention of antimetastasis markers, viz E-cadherin, and alpha- and beta-catenin, along with a significant decrease in vascular endothelial growth factor protein expression. Celecoxib supplementation also resulted in enhanced in vivo apoptosis in the prostate as monitored by several techniques including a recently perfected technique of 99mTc-labeled annexin V in live animals followed by phosphor imaging. One striking observation in an additional study was that celecoxib feeding to mice with established tumors (16 weeks of age) significantly improved their overall survival (P = 0.014), compared with AIN 76A-fed group. Our findings suggest that celecoxib may be useful in chemoprevention of prostate cancer.

Adenocarcinoma↗
PubMed2004

Essential role of caspases in epigallocatechin-3-gallate-mediated inhibition of nuclear factor kappa B and induction of apoptosis.

Green tea constituent (-) epigallocatechin-3-gallate (EGCG) has shown remarkable cancer-preventive and some cancer-therapeutic effects. This is partially because of its ability to induce apoptosis in cancer cells without affecting normal cells. Previous studies from our laboratory have shown the involvement of NF-kappa B pathway in EGCG-mediated cell-cycle deregulation and apoptosis of human epidermoid carcinoma A431 cells. Here we show the essential role of caspases in EGCG-mediated inhibition of NF-kappa B and its subsequent apoptosis. Treatment of A431 cells with EGCG (10-40 microg/ml) resulted in dose-dependent inhibition of NF-kappa B/p65, induction of DNA breaks, cleavage of poly(ADP-ribose) polymerase (PARP) and morphological changes consistent with apoptosis. EGCG treatment of cells also resulted in significant activation of caspases, as shown by the dose- and time-dependent increase in DEVDase activity, and protein expression of caspase-3, -8 and -9. EGCG-mediated caspase activation induces proteolytic cleavage of NF-kappa B/p65 subunit, leading to the loss of transactivation domains, and driving the cells towards apoptosis. EGCG-mediated induction of apoptosis was significantly blocked by the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (Z-VAD-FMK), and moderately blocked by the specific caspase-3 inhibitor Z-DEVD-FMK. Further, pretreatment of cells with Z-VAD-FMK was found to suppress the cleavage of NF-kappa B/p65 subunit, thereby increasing nuclear translocation, DNA binding and transcriptional activity, thus protecting the cells from EGCG-induced apoptosis. Taken together, these studies for the first time demonstrate that EGCG-mediated activation of caspases is critical, at least in part, for inhibition of NF-kappa B and subsequent apoptosis.

Amino Acid Chloromethyl Ketones↗
PubMed2004

Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion markers in CD-1 mouse skin by oleandrin.

Oleandrin, derived from the leaves of Nerium oleander, has been shown to possess anti-inflammatory and tumor cell growth-inhibitory effects. Here, we provide evidence that oleandrin could possess anti-tumor promoting effects. We determined the effect of topical application of oleandrin to CD-1 mice against l2-O-tetradecanoylphorbol-13-acetate (TPA), a widely studied skin tumor promoter, -induced conventional and novel markers of skin tumor promotion. Topical application of oleandrin (2 mg per mouse) 30 min before TPA (3.2 nmol per mouse) application onto the skin afforded significant inhibition, in a time-dependent manner, against TPA-mediated increase in cutaneous edema and hyperplasia, epidermal ornithine decarboxylase (ODC) activity and ODC and cyclooxgenase-2 (COX-2) protein expression. In search for novel markers of skin tumor promotion, we found that TPA application to mouse skin resulted, as an early event, in an increased expression of phosphatidyinositol 3-kinase (PI3K), phosphorylation of Akt at threonine308 and activation of nuclear factor kappa B (NF-kappaB). Topical application of oleandrin before TPA application to mouse skin resulted in significant reduction in TPA-induced expression of PI3K and phosphorylation of Akt, and inhibition of NF-kappaB activation. NF-kappaB is a eukaryotic transcription factor that is critically involved in regulating the expression of specific genes that participate in inflammation, apoptosis and cell proliferation. Employing Western blot analysis, we found that oleandrin application to mouse skin resulted in inhibition of TPA-induced activation of NF-kappaB, IKKalpha and phosphorylation and degradation of IkappaBalpha. Our data suggest that oleandrin could be a useful anti-tumor promoting agent because it inhibits several biomarkers of TPA-induced tumor promotion in an in vivo animal model. One might envision the use of chemopreventive agents such as oleandrin in an emollient or patch for chemoprevention or treatment of skin cancer.

Administration, Cutaneous↗
PubMed2004

Modulation of phosphatidylinositol-3-kinase/protein kinase B- and mitogen-activated protein kinase-pathways by tea polyphenols in human prostate cancer cells.

We have earlier shown that oral infusion of a polyphenolic fraction isolated from green tea, at a human achievable dose (equivalent to six cups of green tea per day), significantly inhibits prostate cancer (PCA) development and metastasis in transgenic adenocarcinoma of mouse prostate (TRAMP) model that closely mimics progressive form of human prostatic disease (Gupta et al. [2001]: Proc. Natl. Acad. Sci. U.S.A. 98:10350-10355.). A complete understanding of the mechanism(s) and molecular targets of PCA chemopreventive effects of tea polyphenols may be useful in developing novel approaches for its prevention. In this study, we employed two distinct human PCA cell lines viz. DU145 (androgen-unresponsive prostate carcinoma cells) and LNCaP (androgen-responsive prostate carcinoma cells) and, employing immunoblot analysis, we evaluated the effect of epigallocatechin-3-gallate (EGCG), the major polyphenol present in green tea and theaflavins (TF), the major polyphenol present in black tea on phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB) and mitogen-activated protein kinase (MAPK) pathways. Both EGCG and TF treatment were found to (i) decrease the levels of PI3K and phospho-Akt and (ii) increase Erk1/2 in both DU145 and LNCaP cells. Our data showing the inhibition of the constitutive levels of PI3K and the phosphorylation of Akt could be important because the treatment approaches should be aimed at the inhibition of the constitutive levels of PI3K and Akt. Our data also suggest that Erk1/2 could be involved in the anti-cancer effects of EGCG and TF. Taken together, our study, for the first time demonstrated the modulation of the constitutive activation of PI3K/Akt and Erk1/2 pathways by EGCG as well as TF. We suggest that detailed studies in appropriate tumor model system are needed to establish the relevance of the cell culture work to in vivo models.

Antineoplastic Agents↗
PubMed2004

Antioxidants of the beverage tea in promotion of human health.

Tea that contains many antioxidants is a pleasant and safe drink that is enjoyed by people across the globe. Tea leaves are manufactured as black, green, or oolong. Black tea represents approximately 78% of total consumed tea in the world, whereas green tea accounts for approximately 20% of tea consumed. The concept of "use of tea for promotion of human health and prevention and cure of diseases" has become a subject of intense research in the last decade. Diseases for which tea drinkers appear to have lower risk are simple infections, like bacterial and viral, to chronic debilitating diseases, including cancer, coronary heart disease, stroke, and osteoporosis. Initial work on green tea suggested that it possesses human health-promoting effects. In recent years, the research efforts have been expanded to black tea as well. Research conducted in recent years reveals that both black and green tea have very similar beneficial attributes in lowering the risk of many human diseases, including several types of cancer and heart diseases. For cancer prevention, evidence is so overwhelming that the Chemoprevention Branch of the National Cancer Institute has initiated a plan for developing tea compounds as cancer-chemopreventive agents in human trials. Thus, modern medical research is confirming the ancient wisdom that therapy of many diseases may reside in an inexpensive beverage in a "teapot."

Animals↗