[Show abstract][Hide abstract] ABSTRACT: The rising incidence of skin cancer in humans makes it equivalent to malignancies of organs. Therefore, it is necessary to intensify our efforts for better understanding and development of novel treatment and preventive approaches for skin cancer. Fruits and other plant derived products have gained considerable attention as they can reduce the risk of several cancer types. Lupeol, a triterpene, present in many fruits and medicinal plants, has been shown to possess many pharmacological properties including anti-cancer effect in both in vitro and in vivo assay systems. In the present study, apoptosis inducing effects of lupeol were studied in human epidermoid carcinoma A431 cells. Cell cycle analysis showed that lupeol treatment induces apoptosis (14-37%) in a dose-dependent manner as evident by an increased sub G(1) cell population. The RT-PCR and Western blot analysis showed that lupeol-induced apoptosis was associated with caspase dependent mitochondrial cell death pathway through activation of Bax, caspases, Apaf1, decrease in Bcl-2 expression and subsequent cleavage of PARP. Lupeol treatment also inhibited Akt/PKB signaling pathway by inhibition of Bad (Ser136) phosphorylation and 14-3-3 expression. In addition, lupeol treatment inhibited cell survival by inactivation of NFkappaB through upregulation of its inhibitor Ikappabetaalpha. The Caspase mediated apoptosis was noticed by decrease in lupeol induced apoptosis by Caspase inhibitors as well as increase in reactive oxygen species generation and loss of mitochondrial membrane potential. These results suggest that lupeol could be an effective anti-cancer agent and merits further investigation.
Cancer biology & therapy 10/2009; 8(17):1632-9. · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To unravel the molecular mechanisms underlying the chemopreventive potential of -gingerol, a pungent ingredient of ginger rhizome (Zingiber officinale Roscoe, Zingiberaceae), against benzo[a]pyrene (B[a]P)-induced mouse skin tumorigenesis.
Topical treatment of -gingerol (2.5 muM/animal) was given to the animals 30 min prior and post to B[a]P (5 mug/animal) for 32 weeks. At the end of the study period, the skin tumors/tissues were dissected out and examined histopathologically. Flow cytometry was employed for cell cycle analysis. Further immunohistochemical localization of p53 and regulation of related apoptogenic proteins were determined by Western blotting.
Chemopreventive properties of -gingerol were reflected by delay in onset of tumorigenesis, reduced cumulative number of tumors, and reduction in tumor volume. Cell cycle analysis revealed that the appearance of sub-G1 peak was significantly elevated in -gingerol treated animals with post treatment showing higher efficacy in preventing tumorigenesis induced by B[a]P. Moreover, elevated apoptotic propensity was observed in tumor tissues than the corresponding non-tumor tissues. Western blot analysis also showed the same pattern of chemoprevention with -gingerol treatment increasing the B[a]P suppressed p53 levels, also evident by immunohistochemistry, and Bax while decreasing the expression of Bcl-2 and Survivin. Further, -gingerol treatment resulted in release of Cytochrome c, Caspases activation, increase in apoptotic protease-activating factor-1 (Apaf-1) as mechanism of apoptosis induction.
On the basis of the results we conclude that -gingerol possesses apoptotic potential in mouse skin tumors as mechanism of chemoprevention hence deserves further investigation.
Cancer Chemotherapy and Pharmacology 08/2009; 65(4):687-96. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Many naturally occurring phytochemicals have shown cancer chemopreventive potential in a variety of bioassay systems. One such naturally occurring biologically active compound is tea Camellia sinensis, which is the most consumed beverage in the world after water. The most abundant and active constituents of tea are polyphenols (epigallocatechin gallate and theaflavins). In the present study, cancer chemopreventive properties of both black tea polyphenols (BTP) and green tea polyphenols (GTP) on 7,12-dimethylbenz[a]anthracene (DMBA) induced mouse skin carcinogenesis were studied. BTP and GTP treatment showed delay in onset of tumorigenesis, reduction in cumulative number of tumors and increased tumor free survival. Both BTP and GTP were found to modulate the expression of proteins involved in apoptotic pathway. Tea polyphenols treatment along with DMBA exposure resulted in upregulation of p53, and proapoptotic protein Bax, whereas enhanced expression of antiapoptotic proteins, Bcl-2 and survivin by DMBA were downregulated. Further, we showed that tea polyphenols supplementation resulted in release of cytochrome c, caspases activation, and increase in apoptotic protease activating factor and poly (ADP-ribose) polymerase cleavage as mechanism of apoptosis induction. The results also provide strong evidence that BTP is a better chemopreventive agent against skin tumorigenesis as compared to GTP at the tested dose levels. Thus, we can conclude that the polyphenolic constituents present in black tea and green tea induce mitochondrial pathway of apoptosis and hence can be used as a potential chemopreventive agents against skin cancer.
Cancer biology & therapy 08/2009; 8(13):1281-7. · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Due to lack of validated screening methods and hence poor prognosis, treatment of lung cancer has not still improved up to the expectations. Therefore, risk of lung cancer needs to be minimized by efficient preventive measures. Tea (Camellia sinensis) and its bioactive polyphenols have been associated with prevention of human cancer for several organs. Thus, intake of tea polyphenols seems to be a viable mean to control lung cancer burden. In the present study, we studied the chemopreventive effects of green tea polyphenols (GTP) and black tea polyphenols (BTP) against diethylnitrosoamine (DEN) induced lung tumors in Swiss albino mice.
Chemopreventive potential of tea polyphenols, was recorded as evident by, low incidence of alveologenic tumors in lungs of animals at tested doses (0.1% and 0.2% of both GTP and BTP) when compared with DEN (20 mg/kg b wt) treated animals. As a mechanism of cancer chemoprevention cellular signaling pathways were also targeted. GTP and BTP treatment inhibited the expression of Akt, cyclooxygenase-2 and inactivated nuclear factor-kappa B via blocking phosphorylation and subsequent degradation of IkappaB alpha.
Thus, the study suggests that polyphenolic constituents of both cultivars of tea, i.e. green and black, have chemopreventive effects in DEN induced lung tumorigenesis in Swiss albino mice.
Investigational New Drugs 07/2009; 28(4):466-71. · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since skin cancer incidence and prevalence is constantly rising up the charts despite all efforts, search for newer, better agents for protection and treatment is required. Ginger (Zingiber officinale Roscoe), a monocotyledonous herb, is widely used as a herbal medicine, given the presence of homologous phenolic ketones, of which -gingerol is the major one. The quantity of -gingerol in the fresh ginger rhizome was found to be 104-965 microg/g in common varieties of ginger available in Indian market. Herein, -gingerol was assessed for its anti-apoptotic effects in human epidermoid carcinoma A431 cells. -Gingerol treatment exhibited considerable cytotoxicity as indicated by growth inhibition of A431 cells mediated via generation of reactive oxygen species (ROS). Increase in ROS led to decrease in mitochondrial membrane potential (MMP) and subsequent induction of apoptosis. Results revealed that perturbations in mitochondrial membrane are associated with deregulation of Bax/Bcl-2 ratio at gene transcriptional level as well as protein level, where treatment with -gingerol leads to up-regulation of Cytochrome-c and Apaf-1 subsequently culminating in triggering of Caspase cascade. These firmly suggest that -gingerol can be effectively used for the treatment of skin cancer.
[Show abstract][Hide abstract] ABSTRACT: Resveratrol has been reported to suppress cancer progression in several in vivo and in vitro models, whereas ultraviolet B (UVB), a major risk for skin cancer, is known to induce cell death in cancerous cells. Here, we investigated whether resveratrol can sensitize A431 human epidermoid carcinoma cells to UVB-induced cell death. We examined the combined effect of UVB (30 mJ/cm(2)) and resveratrol (60 microM) on A431 cells. Exposure of A431 carcinoma cells to UVB radiation or resveratrol can inhibit cell proliferation and induce apoptosis. However, the combination of resveratrol and UVB exposure was associated with increased proliferation inhibition of A431 cells compared with either agent alone. Furthermore, results showed that resveratrol and UVB treatment of A431 cells disrupted the nuclear factor-kappaB (NF-kappaB) pathway by blocking phosphorylation of serine 536 and inactivating NF-kappaB and subsequent degradation of IkappaBalpha, which regulates the expression of survivin. Resveratrol and UVB treatment also decreased the phosphorylation of tyrosine 701 of the important transcription factor signal transducer activator of transcription (STAT1), which in turn inhibited translocation of phospho-STAT1 to the nucleus. Moreover, resveratrol/UVB also inhibited the metastatic protein LIMK1, which reduced the motility of A431 cells. In conclusion, our study demonstrates that the combination of resveratrol and UVB act synergistically against skin cancer cells. Thus, resveratrol is a potential chemotherapeutic agent against skin carcinogenesis.
Biochemical and Biophysical Research Communications 05/2009; 384(2):215-20. · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lupeol, present in fruits and medicinal plants, is a biologically active compound that has been shown to have various pharmacological properties in experimental studies. In the present study, we demonstrated the modulatory effect of lupeol on 7,12-dimethylbenz[a]anthracene (DMBA)-induced alterations on cell proliferation in the skin of Swiss albino mice. Lupeol treatment showed significant (p < 0.05) preventive effects with marked inhibition at 48, 72, and 96 h against DMBA-mediated neoplastic events. Cell-cycle analysis showed that lupeol-induced G2/M-phase arrest (16-37%) until 72 h, and these inhibitory effects were mediated through inhibition of the cyclin-B-regulated signaling pathway involving p53, p21/WAF1, cdc25C, cdc2, and cyclin-B gene expression. Further lupeol-induced apoptosis was observed, as shown by an increased sub-G1 peak (28%) at 96 h, with upregulation of bax and caspase-3 genes and downregulation of anti-apoptotic bcl-2 and survivin genes. Thus, our results indicate that lupeol has novel anti-proliferative and apoptotic potential that may be helpful in designing strategies to fight skin cancer.
Biochemical and Biophysical Research Communications 03/2009; 381(2):253-8. · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer (PCa) is the most frequently diagnosed noncutaneous cancer and the leading cause of cancer related deaths in men in the United States and many other Asian countries. Dietary factors are considered as a strategic agent to control the risk of PCa. Lupeol, a triterpene, present in fruits and medicinal plants, has been shown to possess many pharmacological properties including anticancer effects. Here, effect of lupeol on cell proliferation and cell death was evaluated using human PCa cells, PC-3. In MTT assay, lupeol inhibited the cell proliferation (12-71%) in dose (50-800 microM) and time dependent manner. Flow-cytometric analysis of cell-cycle revealed that an antiproliferative effect of lupeol (400-600 microM) is associated with an increase in G(2)/M-phase arrest (34-58%). RT-PCR analysis showed that lupeol-induced G2/M-phase arrest was mediated through the inhibition of cyclin regulated signaling pathway. Lupeol inhibited the expression of cyclin B, cdc25C, and plk1 but induced the expression of 14-3-3sigma genes. However no changes were observed in the expression of gadd45, p21(waf1/cip1) and cdc2 genes. Results of western blot showed that lupeol regulates the phosphorylation of cdc2 (Tyr15) and cdc25C (Ser198). Further, on increase of lupeol exposure to PC-3 cells an induction of apoptosis was recorded, which was associated with upregulation of bax, caspase-3, -9, and apaf1 genes and down regulation of antiapoptotic bcl-2 gene. The role of caspase-induced apoptosis was confirmed by increase in reactive oxygen species, loss of mitochondrial membrane potential followed by DNA fragmentation. Thus, our study suggests that lupeol possess novel antiproliferative and apoptotic potential against PCa.
[Show abstract][Hide abstract] ABSTRACT: Mutations that occur through DNA strand breaks are the precursors of the variety of genetic disorders including cancer. Life style and dietary habits are considered as major determinants in causation and prevention of genetic diseases. Epidemiological and laboratory studies suggest that plant derived compounds have the potential to prevent a number of genetic diseases. Therefore, use of nutraceuticals can be an important and convenient tool for chemoprevention. Polyphenolic phytochemicals such as epigallocatechin gallate flavonoids quercetin, genistein, curcumin and resveratrol constitute a class of nutraceuticals with notable efficacy in preclinical models of carcinogenesis. Lupeol, a pentacyclic triterpene present in mango, is a biologically active compound that has been reported to possess a number of pharmacological properties in the in vivo and in vitro studies. In the present study, we investigated the effects of lupeol on 7,12-dimethylbenz[a]anthracene (DMBA), induced DNA strand breaks in mouse skin, using an alkaline unwinding assay. Increasing doses of lupeol (50-200 microg/mouse) were given topically, prior or after the single topical application of DMBA (100 microg/mouse) with the sampling time of 24, 48, 72 and 96 h, respectively. Both pre and post treatment of lupeol showed significant (p<0.001) preventive effects in DMBA induced DNA strand breaks in dose and time dependent manner. The pre-treatment of lupeol at the dose of 200 microg/mouse showed 56.05% prevention, and post-treatment at the same dose showed 43.26% prevention, at 96 h time interval, against DMBA induced DNA strand breakage. The results suggest preventive effects of lupeol on DMBA induced DNA alkylation damage in Swiss albino mice.
Food and Chemical Toxicology 12/2007; 45(11):2331-5. · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutations that occur through DNA strand breaks are the prerequisites for the development of tumors, which ultimately leads to various genetic disorders including cancer. A number of naturally occurring compounds including certain dietary constituents play an important role in causation and prevention of a number of genetic diseases. Diallyl sulfide (DAS), a volatile organosulfur compound present in garlic has been shown to possess various pharmacological effects including cancer preventive properties. Now we are reporting the antimutagenic properties of DAS on 7,12- dimethylbenz[a]anthracene (DMBA), a carcinogenic polycyclic aromatic hydrocarbon, induced DNA strand breaks in mouse skin, using an alkaline unwinding assay. DAS (2.5-10 mg/kg body-weight) was applied topically, prior and post to DMBA (5 mg/kg body-weight) at the sampling time of 24, 48, 72 and 96 h. DAS application resulted in a significant (p < 0.001) protection in DMBA-induced DNA strand breaks. The pre-treatment of DAS (10 mg/kg body-weight) showed 68.35% protection and post-treatment showed 59.49% protection, at an intermittent period of 48 h, against DMBA-induced DNA strand breakage. These findings suggest that DAS can effectively check the mutations induced by environmental toxicants.
[Show abstract][Hide abstract] ABSTRACT: Cancer is the major public health problem, causing approximately 7 million deaths every year worldwide. The existing treatment
approaches and surgical techniques have not been able to cope effectively with this dreaded disease. Because of this, the
concept of chemoprevention is now considered a valid approach to reduce the incidence of cancer. There is convincing epidemiological
and experimental evidence to show that dietary polyphenolic plant-derived compounds have cancer preventive properties. Based
on evidence from in vitro, in vivo data and epidemiological studies, tea has received considerable attention over recent years for reducing the risk of several
cancers. Much of the cancer preventive effects of tea, and in particular green tea, appear to be mediated by the polyphenols
they contain. In addition to inhibiting mutagenesis and proliferation, tea is relatively non-toxic, is low cost, and can be
taken orally or as a part of the daily diet. Therefore it is logical that future clinical studies should focus on examining
the efficacy of tea and its active constituents, such as epigallocatechin-3-gallate (EGCG) and theaflavins (TFs), in chemoprevention
as an alternative to pharmacological agents. In this review, we address the use of tea and its constituents for the prevention
and treatment of cancer. Further mechanistic and dose-response studies will help us to understand the effects of tea consumption
on human carcinogenesis.