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Hasan Mukhtar

Publications and source records attributed to Hasan Mukhtar.

At least 55 records · Page 3Linked to original sources
PubMed2004

Cytochrome p450: a target for drug development for skin diseases.

Enzymes of the cytochrome P450 (P450 or CYP) super family are the most versatile and important class of drug-metabolizing enzymes that are induced in mammalian skin in response to xenobiotic exposure. At the same time, CYP have numerous important roles in endogenous and exogenous substrate metabolism in the skin. For example, they participate in the metabolism of therapeutic drugs, fatty acids, eicosonoids, sterols, steroids, vitamin A, and vitamin D, to name a few. In addition, in some skin diseases, for example in psoriasis, many CYP are elevated. CYP are the target of special interest in the development of drugs for skin diseases because most, if not all, drugs available in the armamentarium of the dermatologists are either substrate, inducer, or inhibitor of this enzyme family. The functional significance of drug metabolism in skin and the implication of CYP in skin pathology and therapy is an area for future investigation. A detailed insight into the mechanism of action of various cutaneous CYP, being capable of modulating the drug bioavailability, will be helpful in the development of better strategies for novel therapy against constantly increasing skin disorders. This brief review discusses some of these perspectives and suggests additional work in this research area with regard to the expression and modulation of CYP in mammalian skin as well as their implication in dermatological disorders and the therapy of skin diseases.

Animals↗
PubMed2004

Sanguinarine causes cell cycle blockade and apoptosis of human prostate carcinoma cells via modulation of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery.

Prostate cancer is the second leading cause of cancer-related deaths in males in the United States. This warrants the development of novel mechanism-based strategies for the prevention and/or treatment of prostate cancer. Several studies have shown that plant-derived alkaloids possess remarkable anticancer effects. Sanguinarine, an alkaloid derived from the bloodroot plant Sanguinaria canadensis, has been shown to possess antimicrobial, anti-inflammatory, and antioxidant properties. Previously, we have shown that sanguinarine possesses strong antiproliferative and proapoptotic properties against human epidermoid carcinoma A431 cells and immortalized human HaCaT keratinocytes. Here, employing androgen-responsive human prostate carcinoma LNCaP cells and androgen-unresponsive human prostate carcinoma DU145 cells, we studied the antiproliferative properties of sanguinarine against prostate cancer. Sanguinarine (0.1-2 micromol/L) treatment of LNCaP and DU145 cells for 24 hours resulted in dose-dependent (1) inhibition of cell growth [as evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay], (2) arrest of cells in G0-G1 phase of the cell cycle (as assessed by DNA cell cycle analysis), and (3) induction of apoptosis (as evaluated by DNA ladder formation and flow cytometry). To define the mechanism of antiproliferative effects of sanguinarine against prostate cancer, we studied the effect of sanguinarine on critical molecular events known to regulate the cell cycle and the apoptotic machinery. Immunoblot analysis showed that sanguinarine treatment of both LNCaP and DU145 cells resulted in significant (1) induction of cyclin kinase inhibitors p21/WAF1 and p27/KIP1; (2) down-regulation of cyclin E, D1, and D2; and (3) down-regulation of cyclin-dependent kinase 2, 4, and 6. A highlight of this study was the fact that sanguinarine induced growth inhibitory and antiproliferative effects in human prostate carcinoma cells irrespective of their androgen status. To our knowledge, this is the first study showing the involvement of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery during cell cycle arrest and apoptosis of prostate cancer cells by sanguinarine. These results suggest that sanguinarine may be developed as an agent for the management of prostate cancer.

Alkaloids↗
PubMed2003

Suppression of UVB-induced phosphorylation of mitogen-activated protein kinases and nuclear factor kappa B by green tea polyphenol in SKH-1 hairless mice.

Studies from our laboratory have shown that epigallocatechin-3-gallate, the major polyphenol present in green tea, inhibits ultraviolet (UV)B-exposure-mediated phosphorylation of mitogen-activated protein kinases (MAPKs) (Toxicol. Appl. Pharmacol. 176: 110-117, 2001) and activation of nuclear factor kappa B (NF-kappaB) (Oncogene 22: 1035-1044, 2003) pathways in normal human epidermal keratinocytes. This study was designed to investigate the relevance of these findings to the in vivo situations in SKH-1 hairless mouse model, which is regarded to have relevance to human situations. SKH-1 hairless mice were topically treated with GTP (5 mg/0.2 ml acetone/mouse) and were exposed to UVB 30 min later (180 mJ/cm2). These treatments were repeated every alternate day for 2 weeks, for a total of seven treatments. The animals were killed 24 h after the last UVB exposure. Topical application of GTP resulted in significant decrease in UVB-induced bifold-skin thickness, skin edema and infiltration of leukocytes. Employing Western blot analysis and immunohistochemical studies, we found that GTP resulted in inhibition of UVB-induced: (i) phosphorylation of extracellular-signal-regulated kinases (ERK1/2), (ii) c-Jun N-terminal kinases, and (iii) p38 protein expression. Since NF-kappaB plays a major role in inflammation and cell proliferation, we assessed the effect of GTP on UVB-mediated modulations in the NF-kappaB pathway. Our data demonstrated that GTP inhibited UVB-induced: (i) activation of NF-kappaB, (ii) activation of IKKalpha, and (iii) phosphorylation and degradation of IkappaBalpha. Our data suggest that GTP protects against the adverse effects of UV radiation via modulations in MAPK and NF-kappaB signaling pathways, and provides molecular basis for the photochemopreventive effect of GTP in an in vivo animal model system.

Animals↗
PubMed2003

Cyclooxygenases in the skin: pharmacological and toxicological implications.

Cyclooxygenase (COX), a prostaglandin-endoperoxide synthase (PTGS), catalyzes the formation of prostaglandins from arachidonic acid. Prostaglandins are lipid signaling mediators that play a central role in a broad range of diverse physiological and pathophysiological processes, including inflammation, reproduction, nocioception, and gastrointestinal protection. Inhibition of cyclooxygenase activity is the mechanism by which nonsteroidal antiinflammatory drugs (NSAIDS) exert their analgesic, antipyretic, antiinflammatory, and antithrombotic effects. COX is currently believed to exist in three isoforms. In this review, we provide a concise state-of-the-art description of the role of COX in pharmacology and toxicology of skin including its involvement in normal physiology, cutaneous inflammation, nociception, wound healing, and tumorigenesis. COX-dependent pathways influence keratinocyte differentiation, hair follicle development, and hair growth. The critical role of COX-2 in pathophysiology of skin is also addressed. COX-2 mediates inflammatory processes in skin, including inflammatory hyperalgesia and nociception, and administration of specific COX-2 inhibitors reduces edema, vascular permeability, and other markers of cutaneous inflammation. A number of studies in animal models and in humans show that COX-2 inhibitors possess cancer chemopreventive properties. Selective COX-2 inhibitors have a more favorable side-effect profile. Topical formulations of COX-2 inhibitors are being developed as a novel pharmacologic approach for the treatment of COX-2 mediated skin diseases.

Animals↗
PubMed2003

Gallstone ileus.

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Aged↗
PubMed2003

Activation of prodeath Bcl-2 family proteins and mitochondrial apoptosis pathway by sanguinarine in immortalized human HaCaT keratinocytes.

Sanguinarine, derived from the root of Sanguinaria canadensis and other poppy fumaria species, possesses strong antimicrobial, anti-inflammatory, and antioxidant properties. We earlier showed that sanguinarine kills human epidermoid carcinoma A431 cells via an induction of apoptosis [N. Ahmad et al., Clin. Cancer Res., 6: 1524-1528, 2000]. In this study, using immortalized human keratinocytes (HaCaT cells), we provide information about mechanism of the antiproliferative effect of sanguinarine. Sanguinarine [0.1 (M-2 (M)] treatment to HaCaT cells was found to inhibit in a dose-dependent manner the cell proliferation and induce apoptosis, as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ELISA, respectively. Sanguinarine treatment also resulted in a significant cleavage of poly(ADP-ribose) polymerase in HaCaT cells. Because mitochondrial pathway is critical for the regulation of apoptosis, we studied the involvement and regulation of mitochondrial events in sanguinarine-mediated apoptosis of HaCaT cells. As shown by the immunoblot analysis, our data clearly demonstrated that sanguinarine treatment to HaCaT cells resulted in a dose-dependent (a) increase in the level of Bax with a concomitant decrease in Bcl-2 levels and (b) increase in Bax/Bcl-2 ratio. Sanguinarine also resulted in significant increases in the proapoptotic members of Bcl-2 family proteins, i.e., Bak and Bid. This was accompanied by increase in (a) protein expression of cytochrome c and apoptotic protease-activating factor-1 and (b) activity and protein expression of caspase-3, caspase-7, caspase-8, and caspase-9. Taken together, our data showed the involvement of mitochondrial pathway and Bcl-2 family proteins during sanguinarine-mediated apoptosis of immortalized keratinocytes. We suggest that sanguinarine could be developed as a drug for the management of hyperproliferative skin disorders, including skin cancer.

Alkaloids↗
PubMed2003

Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells.

We have recently shown that oral consumption of green tea polyphenols inhibits prostate carcinogenesis in transgenic mouse model of prostate cancer and suggested that induction of apoptosis in prostate cancer cells is responsible for these effects. Much of the chemopreventive effects of green tea are attributed to its major polyphenolic constituent (-) epigallocatechin-3-gallate (EGCG). In the present study, we report that EGCG-induced apoptosis in human prostate carcinoma LNCaP cells is mediated via modulation of two related pathways: (a) stabilization of p53 by phosphorylation on critical serine residues and p14ARF-mediated downregulation of murine double minute 2(MDM2) protein, and (b) negative regulation of NF-kappaB activity, thereby decreasing the expression of the proapoptotic protein Bcl-2. EGCG-induced stabilization of p53 caused an upregulation in its transcriptional activity, thereby resulting in activation of its downstream targets p21/WAF1 and Bax. Thus, EGCG had a concurrent effect on two important transcription factors p53 and NF-kappaB, causing a change in the ratio of Bax/Bcl-2 in a manner that favors apoptosis. This altered expression of Bcl-2 family members triggered the activation of initiator capsases 9 and 8 followed by activation of effector caspase 3. Activation of the caspases was followed by poly (ADP-ribose) polymerase cleavage and induction of apoptosis. Taken together, the data indicate that EGCG induces apoptosis in human prostate carcinoma cells by shifting the balance between pro- and antiapoptotic proteins in favor of apoptosis.

Adenocarcinoma↗
PubMed2003

Cyclooxygenase-2 and prostate carcinogenesis.

In recent years a dramatic surge has occurred on studies defining to the role of cyclooxygenase (COX)-2 in causation and prevention of cancer. Prostaglandin (PG) endoperoxidase synthase also commonly referred to as COX is a key enzyme involved in the conversion of arachidonic acid to PGs and other eicosanoids. COX exists as two isoforms, namely COX-1 and COX-2 with distinct tissue distribution and physiological functions. COX-1 is constitutively expressed in many tissues and cell types and is involved in normal cellular physiological functions whereas COX-2 is pro-inflammatory in nature and is inducible by mitogens, cytokines, tumor promoters and growth factors. A large volume of data exists showing that COX-2 is overexpressed in a large number of human cancers and cancer cell lines. The possibility of COX-2 as a candidate player in cancer development and progression evolved from the epidemiological studies which suggest that regular use of aspirin or other non-steroidal anti-inflammatory drugs could significantly decrease the risk of developing cancers in experimental animals and in humans. In our recently published study (Prostate, 42 2000 73-78), we provided the first evidence that COX-2 is overexpressed in human prostate adenocarcinoma. Many other studies verified our initial observation and reported that compared to normal tissue, COX-2 is overexpressed in human prostate cancer. It should be noted that some recent work has suggested that COX-2 is only up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. In this scenario, COX-2 inhibitors could afford their effects against prostate carcinogenesis by modulating COX-2 activity in other cells in prostate. An exciting corollary to this ongoing work is that selective COX-2 inhibitors may exhibit chemopreventive and even chemotherapeutic effects against prostate carcinogenesis in humans.

Adenocarcinoma↗
PubMed2003

Inhibition of ultraviolet B-mediated activation of nuclear factor kappaB in normal human epidermal keratinocytes by green tea Constituent (-)-epigallocatechin-3-gallate.

Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, possesses significant anti-inflammatory and cancer chemopreventive properties. Studies have shown the photochemopreventive effects of green tea and EGCG in cell culture, animal models, and human skin. The molecular mechanism(s) of photochemopreventive effects of EGCG are incompletely understood. We recently showed that EGCG treatment of the normal human epidermal keratinocytes (NHEK) inhibits ultraviolet (UV)B-mediated activation of the mitogen-activated protein kinase (MAPK) pathway. In this study, we evaluated the effect of EGCG on UVB-mediated modulation of the nuclear factor kappa B (NF-kappaB) pathway, which is known to play a critical role in a variety of physiological functions and is involved in inflammation and development of cancer. Immunoblot analysis demonstrated that the treatment of NHEK with EGCG (10-40 microM) for 24 h resulted in a significant inhibition of UVB (40 mJ/cm(2))-mediated degradation and phosphorylation of IkappaBalpha and activation of IKKalpha, in a dose-dependent manner. UVB-mediated degradation and phosphorylation of IkappaBalpha and activation of IKKalpha was also observed in a time-dependent protocol (15 and 30 min, 1, 2, 3, 6, 12 h post-UVB exposure). Employing immunoblot analysis, enzyme-linked immunosorbent assay, and gel shift assay, we demonstrate that EGCG treatment of the cells resulted in a significant dose- and time-dependent inhibition of UVB-mediated activation and nuclear translocation of a NF-kappaB/p65. Our data suggest that EGCG protects against the adverse effects of UV radiation via modulations in NF-kappaB pathway, and provide a molecular basis for the photochemopreventive effect of EGCG.

Active Transport, Cell Nucleus↗
PubMed2003

Molecular pathway for (-)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells.

Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, is a promising chemopreventive agent. We recently showed that green tea polyphenols exert remarkable preventive effects against prostate cancer in a mouse model and many of these effects are mediated by the ability of polyphenols to induce apoptosis in cancer cells [Proc. Natl. Acad. Sci. USA 98 (2001) 10350]. Earlier, we showed that EGCG causes a G0/G1 phase cell cycle arrest and apoptosis of both androgen-sensitive LNCaP and androgen-insensitive DU145 human prostate carcinoma cells, irrespective of p53 status [Toxicol. Appl. Pharmacol. 164 (2000) 82]. Here, we provide molecular understanding of this effect. We tested a hypothesis that EGCG-mediated cell cycle dysregulation and apoptosis is mediated via modulation of cyclin kinase inhibitor (cki)-cyclin-cyclin-dependent kinase (cdk) machinery. As shown by immunoblot analysis, EGCG treatment of LNCaP and DU145 cells resulted in significant dose- and time-dependent (i) upregulation of the protein expression of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18, (ii) down-modulation of the protein expression of cyclin D1, cyclin E, cdk2, cdk4, and cdk6, but not of cyclin D2, (iii) increase in the binding of cyclin D1 toward WAF1/p21 and KIP1/p27, and (iv) decrease in the binding of cyclin E toward cdk2. Taken together, our results suggest that EGCG causes an induction of G1 phase ckis, which inhibits the cyclin-cdk complexes operative in the G0/G1 phase of the cell cycle, thereby causing an arrest, which may be an irreversible process ultimately leading to apoptotic cell death. This is the first systematic study showing the involvement of each component of cdk inhibitor-cyclin-cdk machinery during cell cycle arrest and apoptosis of human prostate carcinoma cells by EGCG.

Antineoplastic Agents, Phytogenic↗
PubMed2003

Differential expression of S100A2 and S100A4 during progression of human prostate adenocarcinoma.

PURPOSE: To establish the clinical significance of calcium binding proteins S100A2 and S100A4 during progression of human prostate adenocarcinoma. PATIENTS AND METHODS: Expression pattern of S100A2 and S100A4 was determined in normal human prostate epithelial cells (NHPE); virally transformed prostate epithelial cells (PZ-HPV-7); several human prostate carcinoma cells (22Rv1, DU145, LNCaP, and PC3); tissue samples obtained during transuretheral prostatic resection from patients with benign prostate hyperplasia (BPH), prostatitis, and adenocarcinoma; and paraffin-embedded sections from pair-matched benign and cancer specimens of different tumor grade. RESULTS: High constitutive protein expression of S100A2 was observed in NHPE and PZ-HPV-7 cells, whereas its complete absence was observed in 22Rv1, DU145, LNCaP, and PC3 cells. Tissue samples of BPH and prostatitis exhibited higher mRNA and protein levels of S100A2 than low-grade cancer (Gleason score 6). Immunohistochemical analysis further confirmed high levels of S100A2 in benign tissues and a progressive loss with increasing tumor grade. The protein level of S100A4 was significantly higher in all carcinoma cells compared with NHPE and PZ-HPV-7 cells. The mRNA and protein level of S100A4 was significantly higher in high-grade cancer specimens compared with BPH, prostatitis, and low-grade cancer. The high levels of S100A4 observed in cancer tissue correlated with increasing tumor grade. CONCLUSION: Loss of S100A2 and increased expression of S100A4 may be an important event during progression of prostate cancer in humans.

Adenocarcinoma↗
PubMed2003

Photochemoprevention of skin cancer by botanical agents.

Photochemoprevention has become an important armamentarium in the fight against ultraviolet radiation (UVR)-induced damage to the skin. Among many UVR-induced damages, skin cancer is of the greatest concern as its rates have been steadily increasing in recent years and the same trend is expected to continue in the future. Ultra-violet radiation increases oxidative stress in skin cells by causing excessive generation of reactive oxygen species (ROS), leading to cancer initiation and promotion. Antioxidants have the capability to quench these ROS and much recent work shows that some of these can inhibit many UVR-induced signal transduction pathways. Thus, identifying nontoxic strong antioxidants--capable of preventing UVR-induced skin cancer--has become an important area of research. The use of botanical antioxidants in skin care products is growing in popularity. A wide range of such agents has been shown to prevent skin cancer in animal model systems. New agents are constantly being investigated; however, only a few have been tested for their efficacy in humans. Animal model and cell culture studies have clarified that antioxidants act by several mechanisms at various stages of skin carcinogenesis. This review focuses on skin cancer photochemopreventive effects of selected botanical antioxidants.

Antioxidants↗
PubMed2003

Molecular targets for green tea in prostate cancer prevention.

Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer-related deaths in American males. For these reasons, it is necessary to intensify our efforts for better understanding and development of novel treatment and chemopreventive approaches for this disease. In recent years, green tea has gained considerable attention as an agent that could reduce the risk of several cancer types. The cancer-chemopreventive effects of green tea appear to be mediated by the polyphenolic constituents present therein. Based on geographical observations that suggest that the incidence of PCa is lower in Japanese and Chinese populations that consume green tea on a regular basis, we hypothesized that green tea and/or its constituents could be effective for chemoprevention of PCa. To investigate this hypothesis, we initiated a program for the chemoprevention of PCa by green tea. In cell-culture systems that employ human PCa cells DU145 (androgen insensitive) and LNCaP (androgen sensitive), we found that the major polyphenolic constituent (-)-epigallocatechin-3-gallate (EGCG) of green tea induces 1) apoptosis, 2) cell-growth inhibition, and 3) cyclin kinase inhibitor WAF-1/p21-mediated cell-cycle dysregulation. More recently, using a cDNA microarray, we found that EGCG treatment of LNCaP cells results in 1) induction of genes that functionally exhibit growth-inhibitory effects, and 2) repression of genes that belong to the G-protein signaling network. In animal studies that employ a transgenic adenocarcinoma of the mouse prostate (TRAMP), which is a model that mimics progressive forms of human prostatic disease, we observed that oral infusion of a polyphenolic fraction isolated from green tea (GTP) at a human achievable dose (equivalent to 6 cups of green tea/d) significantly inhibits PCa development and metastasis. We extended these studies and more recently observed increased expression of genes related to angiogenesis such as vascular endothelial growth factor (VEGF) and those related to metastasis such as matrix metalloproteinases (MMP)-2 and MMP-9 in prostate cancer of TRAMP mice. Oral feeding of GTP as the sole source of drinking fluid to TRAMP mice results in significant inhibition of VEGF, MMP-2 and MMP-9. These data suggest that there are multiple targets for PCa chemoprevention by green tea and highlight the need for further studies to identify novel pathways that may be modulated by green tea or its polyphenolic constituents that could be further exploited for prevention and/or treatment of PCa.

Animals↗
PubMed2003

Tea beverage in chemoprevention of prostate cancer: a mini-review.

Because prostate cancer has a long latency period and is typically diagnosed in elderly men, it represents an ideal candidate disease for chemoprevention. Therefore, even a modest delay achieved through intervention could have a significant impact on the outcome of this disease. Epidemiological and laboratory studies have provided convincing evidence that diet, genetic factors, and lifestyle are major causes of prostate cancer. Although surgery, radiotherapy, and hormone therapy are the most widely accepted curative options for a selected group of patients suffering from prostate cancer, the side effects of these treatments are many. In recent years, many dietary agents have been being described that show a wide range of chemopreventive effects in cell culture and selected animal model systems of prostate carcinogenesis. One such agent is the beverage tea, which, next to water, is the most popularly consumed beverage in the world. The epidemiological studies and recent data, amassed from various laboratories around the world, provide evidence that tea polyphenols such as epigallocatechin-3-gallate, epigallocatechin, and epicatechin-3-gallate may have the potential to lower the risk of prostate cancer in the human population. Recently, it has been shown that green tea polyphenols, when given to TRAMP, a transgenic mouse model that mimics progressive forms of human prostate cancer, exert remarkable preventive effects against prostate cancer development. Chemoprevention of prostate cancer by tea polyphenols appears to occur through the modulation of various molecular targets. This article attempts to address the issue of the possible use of tea, especially green tea, for the chemoprevention of prostate cancer.

Androgens↗
PubMed2003

A simplified method for preparation of 99mTc-annexin V and its biologic evaluation for in vivo imaging of apoptosis after photodynamic therapy.

UNLABELLED: Apoptosis is the likely mechanism behind the effects of chemotherapeutic and radiation treatments, rejection of organ transplants, and cell death due to hypoxic-ischemic injury. A simplified method capable of imaging apoptosis in living animals could have many applications leading to understanding of the involvement of apoptosis in biologic and therapeutic processes. To accomplish this goal we developed a method for the preparation of (99m)Tc-annexin V and evaluated its usefulness to detect apoptosis that occurs during tumor shrinkage after photodynamic therapy (PDT). PDT is a cancer treatment modality that leads to rapid induction of apoptosis both in vitro and in in vivo animal models. METHODS: A novel synthesis of (99m)Tc-annexin V was performed in a simple 1-pot procedure. Radiation-induced fibrosarcoma (RIF-1) tumors grown in C(3)H mice were treated with PDT, followed by injection of (99m)Tc-annexin V and measurement of its tumor uptake at 2, 4, and 7 h after PDT by autoradiography. RESULTS: The radiochemical purity of (99m)Tc-annexin V was >95%. At all time points, (99m)Tc-annexin V was clearly imaged in the PDT-treated tumors, whereas the untreated tumors showed no uptake of the radiolabeled compound. Histopathology and immunohistochemistry of PDT-treated tumors confirmed the evidence of apoptosis compared with untreated tumors. CONCLUSION: These data demonstrate the detection of apoptosis using (99m)Tc-annexin V in tumor tissue in living animals after PDT treatment. This novel technique could be used as a noninvasive means to detect and serially image tissues undergoing apoptosis after cancer treatment protocols in humans. Other potential applications of this technique could be the diagnosis of several human disorders, such as myocardial ischemia or infarct, rejection of organ transplantation, and neonatal cerebral ischemia.

Animals↗
PubMed2002

Gene expression profile in human prostate LNCaP cancer cells by (--) epigallocatechin-3-gallate.

Green tea is an effective chemopreventive agent in animal tumor bioassays and some human cancers. Much of its cancer preventive effects appear to be mediated by its major polyphenolic constituent (-) epigallocatechin-3-gallate (EGCG). In order to better understand the molecular regulation underlying the anti-proliferative activity of EGCG in prostate cancer, we have utilized cDNA microarray to elucidate how EGCG alters program of gene expression in prostate carcinoma LNCaP cells. Fluorophore-labeled cDNA probes synthesized from the untreated LNCaP cells or the cells treated for 12 h with EGCG (12 microM), a physiologically achievable dose, were competitively hybridized to the microarray that contained a total of 250 kinases and phosphatases genes. Such high-throughput screening has identified a number of EGCG-responsive gene candidates. Of these, we found that EGCG induced a subset of genes that functionally could exhibit inhibitory effects on cell growth. The genes repressed by EGCG mostly belonged to the G-protein signaling network. Interestingly, the protein kinase C-alpha (PKC-alpha) form, whose inhibition of expression has been shown to inhibit cell growth in some cancer cells, was selectively repressed by EGCG while the expression of six other PKC isoforms (beta, delta, epsilon, micro, eta and zeta) was unaffected. These EGCG-responsive genes may provide key insights from which to understand mechanisms of action of other polyphenolic compounds in prostate cancer chemoprevention.

Anticarcinogenic Agents↗
PubMed2002

Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells.

Apigenin, a common dietary flavonoid abundantly present in fruits and vegetables, may have the potential for prevention and therapy for prostate cancer. Here, we report for the first time that apigenin inhibits the growth of androgen-responsive human prostate carcinoma LNCaP cells and provide molecular understanding of this effect. The cell growth inhibition achieved by apigenin treatment resulted in a significant decrease in AR protein expression along with a decrease in intracellular and secreted forms of PSA. These effects were also observed in DHT-stimulated cells. Further, apigenin treatment of LNCaP cells resulted in G1 arrest in cell cycle progression which was associated with a marked decrease in the protein expression of cyclin D1, D2 and E and their activating partner cdk2, 4 and 6 with concomitant induction of WAF1/p21 and KIP1/p27. The induction of WAF1/p21 appears to be transcriptionally upregulated and is p53 dependent. In addition, apigenin inhibited the hyperphosphorylation of the pRb protein in these cells. Apigenin treatment also resulted in induction of apoptosis as determined by DNA fragmentation, PARP cleavage, fluorescence microscopy and flow cytometry. These effects were found to correlate with a shift in Bax/Bcl-2 ratio more towards apoptosis. Apigenin treatment also resulted in down-modulation of the constitutive expression of NF-kappaB/p65. Taken together, these findings suggest that apigenin has strong potential for development as an agent for prevention against prostate cancer.

Antineoplastic Agents↗