• 대한약침학회지
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• 제22권2호
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• pp.55-67
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• 2019

The incidences of cancer are continuously increasing worldwide, affecting life of millions of people. Several factors associated with the internal and external environment are responsible for this deadly disease. The key internal determinants like abnormal hormonal regulation, genetic mutations and external determinants such as lifestyle and occupational factors enhances onset of cancer. From the ancient time, plants were remained as the most trusted source of medicine for the treatment of diverse disease conditions. Extensive studies have been performed for the discovery of effective anticancer agent from the plant and still it is going on. Pentacyclic triterpenoids are biologically active phytochemicals having a different range of activities such as anti-inflammatory, hepatoprotective, anti-hypertensive, antiulcerogenic and anti-tumor. These compounds generally contain ursane, oleanane, lupane and friedelane as a chief skeleton of pentacyclic triterpenoids which are generally present in higher plants. Isoprene unit, phytochemical, with good antitumor/anticancer activity is required for the biosynthesis of pentacyclic triterpenoids. Mechanisms such as cytotoxicity, DNA polymerase inhibition, regulation of apoptosis, change in signal transductions, interfere with angiogenesis and dedifferentiation, antiproliferative activity and metastasis inhibition are might be responsible for their anticancer effect. Present review spotlights diverse targets, mechanisms and pathways of pentacyclic triterpenoids responsible for anticancer effect.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.273-276
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• 2014

Ellagic acid has been shown to inhibit tumor cell growth. However, the underlying molecular mechanisms remain elusive. In this study, our aim was to investigate whether ellagic acid inhibits the proliferation of MCF-7 human breast cancer cells via regulation of the TGF-${\beta}$/Smad3 signaling pathway. MCF-7 breast cancer cells were transfected with pEGFP-C3 or pEGFP-C3/Smad3 plasmids, and treated with ellagic acid alone or in combination with SIS3, a specific inhibitor of Smad3 phosphorylation. Cell proliferation was assessed by MTT assay and the cell cycle was detected by flow cytometry. Moreover, gene expression was detected by RT-PCR, real-time PCR and Western blot analysis. The MTT assay showed that SIS3 attenuated the inhibitory activity of ellagic acid on the proliferation of MCF-7 cells. Flow cytometry revealed that ellagic acid induced G0/G1 cell cycle arrest which was mitigated by SIS3. Moreover, SIS3 reversed the effects of ellagic acid on the expression of downstream targets of the TGF-${\beta}$/Smad3 pathway. In conclusion, ellagic acid leads to decreased phosphorylation of RB proteins mainly through modulation of the TGF-${\beta}$/Smad3 pathway, and thereby inhibits the proliferation of MCF-7 breast cancer cells.

• Asian Pacific Journal of Cancer Prevention
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• 제16권17호
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• pp.7641-7651
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• 2015

It has been shown previously that nutritional supplements rich in polyphenolic compounds play a significant role in prostate cancer chemoprevention. Propolis is a natural, resinous hive product that has several pharmacological activities including antimicrobial, antioxidant, anti-inflammatory, and antitumoral activities. The aim of this study was to compare the cytotoxic, antioxidant and antitumoral activities of an ethanolic extract of Egyptian propolis (EEP) in vitro with an established chemotherapeutic drug such as doxorubicin (DOX), and the effects of their combination against the PC3 human prostate cancer cell line. Cellular viability and $IC_{50}$ levels with EEP, DOX and their (v/v) combination were detected by sulphorhodamine-B (SRB) assay after incubation of PC3 cells for 72h with different doses (0, 0.01, 0.1, 1, 10 and $100{\mu}g/ml$). Two selected doses of $IC_{50}$ and $IC_{25}$ were applied to cells for 24h for antitumor evaluation assay of treatment compounds. EEP and its (v/v) combination with DOX showed significant antitumor potential besides high antioxidant properties of superoxide dismutase (SOD), total antioxidant capacity (TAC), catalase (CAT), nitric oxide (NO) and reduced glutathione (GSH) levels when compared with the control untreated cells. DNA fragmentation assay and semi quantitative RT-PCR analyses for p53 and Bax genes showed that EEP activated cellular apoptosis and increased the mRNA expression levels more than other treatment. In conclusion, EEP alone or in combination with DOX at both doses used here showed greater antioxidant, antiproliferative and apoptotic effects against the PC3 cell lines as compared to treatment with DOX alone. Therefore, EEP could be considered as a promising candidate for prostate cancer chemotherapy.

• Asian Pacific Journal of Cancer Prevention
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• 제16권15호
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• pp.6549-6556
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• 2015

The PI3K-Akt-mTOR, $Wnt/{\beta}$-catenin and apoptosis signaling pathways have been shown to be involved in genesis of colorectal cancer (CRC). The aim of this study was to elucidate whether combination of Gelam honey and ginger might have chemopreventive properties in HT29 colon cancer cells by modulating the mTOR, $Wnt/{\beta}$-catenin and apoptosis signaling pathways. Treatment with Gelam honey and ginger reduced the viability of the HT29 cells dose dependently with $IC_{50}$ values of 88 mg/ml and 2.15 mg/ml respectively, their while the combined treatment of 2 mg/ml of ginger with 31 mg/ml of Gelam honey inhibited growth of most HT29 cells. Gelam honey, ginger and combination induced apoptosis in a dose dependent manner with the combined treatment exhibiting the highest apoptosis rate. The combined treatment downregulated the gene expressions of Akt, mTOR, Raptor, Rictor, ${\beta}$-catenin, $Gsk3{\beta}$, Tcf4 and cyclin D1 while cytochrome C and caspase 3 genes were shown to be upregulated. In conclusion, the combination of Gelam honey and ginger may serve as a potential therapy in the treatment of colorectal cancer through inhibiton of mTOR, $Wnt/{\beta}$ catenin signaling pathways and induction of apoptosis pathway.

• Asian Pacific Journal of Cancer Prevention
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• 제16권15호
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• pp.6513-6519
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• 2015

Background: Recent attention on chemotherapeutic intervention against cancer has been focused on discovering and developing phytochemicals as anticancer agents with improved efficacy, low drug resistance and toxicity, low cost and limited adverse side effects. In this study, we investigated the effects of Curcuma C20-dialdehyde on growth, apoptosis and cell cycle arrest in colon and cervical cancer cell lines. Materials and Methods: Antiproliferative, apoptosis induction, and cell cycle arrest activities of Curcuma C20-dialdehyde were determined by WST cell proliferation assay, flow cytometric Alexa fluor 488-annexin V/propidium iodide (PI) staining and PI staining, respectively. Results: Curcuma C20 dialdehyde suppressed the proliferation of HCT116, HT29 and HeLa cells, with IC50 values of $65.4{\pm}1.74{\mu}g/ml$, $58.4{\pm}5.20{\mu}g/ml$ and $72.0{\pm}0.03{\mu}g/ml$, respectively, with 72 h exposure. Flow cytometric analysis revealed that percentages of early apoptotic cells increased in a dose-dependent manner upon exposure to Curcuma C20-dialdehyde. Furthermore, exposure to lower concentrations of this compound significantly induced cell cycle arrest at G1 phase for both HCT116 and HT29 cells, while higher concentrations increased sub-G1 populations. However, the concentrations used in this study could not induce cell cycle arrest but rather induced apoptotic cell death in HeLa cells. Conclusions: Our findings suggest that the phytochemical Curcuma C20-dialdehyde may be a potential antineoplastic agent for colon and cervical cancer chemotherapy and/or chemoprevention. Further studies are needed to characterize the drug target or mode of action of the Curcuma C20-dialdehyde as an anticancer agent.

• Biomolecules & Therapeutics
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• 제23권4호
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• pp.339-344
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• 2015

Naringenin (NAR) as one of the flavonoids observed in grapefruit has been reported to exhibit an anti-cancer activity. However, more detailed mechanism by which NAR exerts anti-cancer properties still remains unanswered. Thus, in this study, we have shown that NAR down-regulates the level of cyclin D1 in human colorectal cancer cell lines, HCT116 and SW480. NAR inhibited the cell proliferation in HCT116 and SW480 cells and decreased the level of cyclin D1 protein. Inhibition of proteasomal degradation by MG132 blocked NAR-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in the cells treated with NAR. In addition, NAR increased the phosphorylation of cyclin D1 at threonine-286 and a point mutation of threonine-286 to alanine blocked cyclin D1 downregulation by NAR. p38 inactivation attenuated cyclin D1 downregulation by NAR. From these results, we suggest that NAR-mediated cyclin D1 downregulation may result from proteasomal degradation through p38 activation. The current study provides new mechanistic link between NAR, cyclin D1 downregulation and cell growth in human colorectal cancer cells.

• 한국식품위생안전성학회지
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• 제24권3호
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• pp.267-272
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• 2009

우리 몸에 필수적인 미량원소인 셀레늄은 항암활성이 있는 것으로 알려져 있고, 역학적, 생태학적 그리고 임상시험을 종합해보면, 셀레늄은 종양, 특히 전립선암, 폐암, 대장암에 대한 위험성을 낮출 수 있을 것으로 생각되어진다. 기전연구에 따르면 셀레늄은 DNA single strand breaks와 활성산소종을 유도함으로써 종양을 억제하는 예방효능이 있는 것으로 밝혀지고 있다. 하지만, 아직까지 전립선암세포주에서 methylseloenol 대사체 중에 하나인 MSeA와 세포주기억제와의 관계에 대해서는 명확하게 밝혀져 있지 않은 실정이다. 따라서, 이번 연구에서는 전립선암세포주에서 셀레늄의 세포주기에 관한 효능을 확인해 보고자 하였다. 결과를 종합해보면, MSeA는 전립선암세포주에서 G1/S기 세포주기를 억제하고 DNA 합성을 방해하는 것으로 나타났고, 이러한 현상은 cyclin의존성 키나아제를 길항하는 단백질 중에 하나인 p27단백질의 발현을 증가시킴으로써 일어남을 확인하였다. 따라서, MSeA에 의해 유발되는 세포주기 억제가 전립선암 세포의 성장억제에 기여하는 것으로 사료된다.

• Asian Pacific Journal of Cancer Prevention
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• 제13권4호
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• pp.1177-1182
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• 2012

Protein kinase C (PKC) has been implicated in carcinogenesis and displays variable expression profiles during cancer progression. Studies of dietary phytochemicals on cancer signalling pathway regulation have been conducted to search for potent signalling regulatory agents. The present study was designed to evaluate any suppressive effect of maslinic acid on PKC expression in human B-lymphoblastoid cells (Raji cells), and to identify the PKC isoforms expressed. Effects of maslinic acid on PKC activity were determined using a PepTag$^{(R)}$ assay for non-radioactive detection of PKC. The highest expression in Raji cells was obtained at 20 nM PMA induced for 6 hours. Suppressive effects of maslinic acid were compared with those of four PKC inhibitors (H-7, rottlerin, sphingosine, staurosporine) and two triterpenes (oleanolic acid and ursolic acid). The $IC_{50}$ values achieved for maslinic acid, staurosporine, H-7, sphingosine, rottlerin, ursolic acid and oleanolic acid were 11.52, 0.011, 0.767, 2.45, 5.46, 27.93 and $39.29\;{\mu}M$, respectively. Four PKC isoforms, PKC ${\beta}I$, ${\beta}II$, ${\delta}$, and ${\zeta}$, were identified in Raji cells via western blotting. Maslinic acid suppressed the expression of PKC ${\beta}I$, ${\delta}$, and ${\zeta}$ in a concentration-dependent manner. These preliminary results suggest promising suppressive effects of maslinic acid on PKC activity in Raji cells. Maslinic acid could be a potent cancer chemopreventive agent that may be involved in regulating many downstream signalling pathways that are activated through PKC receptors.

• Asian Pacific Journal of Cancer Prevention
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• 제15권4호
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• pp.1611-1616
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• 2014

Spirogyra neglecta, a freshwater green alga, is a local food in the northern and northeastern parts of Thailand. This investigation explored the anticarcinogenicity of S neglecta and its possible cancer chemopreventive mechanisms in rats divided into 14 groups. Groups 1 and 10 served as positive and negative control groups, respectively. Groups 1-9 were intraperitoneally injected with diethylnitrosamine (DEN) once a week for 3 weeks. Groups 10-14 received normal saline instead. One week after the last DEN injection, groups 2-5 were administered for 9 consecutive weeks various doses of S neglecta extract (SNE) and dried S neglecta (SND), mixed with basal diet. Groups 6-9 and 11-14 similarly were administered various doses of SNE and SND starting from the first week of the experiment. Administration of SNE and SND was not associated with formation of glutathione-Stransferase placental form (GST-P) positive foci in rat liver. SNE and SND during initiation phase significantly reduced the number of GST-P positive foci in rats injected with DEN. The number of GST-P also diminished in groups treated with SNE and SND after injection with DEN, except for the low dose extract group. SNE showed stronger anticarcinogenic potency than SND. Furthermore, SNE also decreased the number of Ki-67 positive cells. However, the numbers of TUNEL-positive cells in the liver of the SNE-treated groups were not statistically different from the controls. The GST activity in 50 mg/kg bw of SNE and 1% of SND groups was significantly increased as compared to the positive control. In conclusion, Spirogyra neglecta (Hassall) K$\ddot{u}$tzing showed cancer chemopreventive properties at the early stages of diethylnitrosamine-induced hepatocarcinogenesis in rats. Possible inhibitory mechanisms include enhancement of the activities of some detoxifying enzymes and/or suppression of precancerous cells.

• Asian Pacific Journal of Cancer Prevention
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• 제13권3호
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• pp.1031-1038
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• 2012

Background: Turmeric ($Curcuma$ $longa$) has been shown to possess anti-inflammatory, antioxidant and antitumor properties. However, despite the progress in research with $C.$ $longa$, there is still a big lacuna in the information on the active principles and their molecular targets. More particularly very little is known about the role of cell cycle genes $p57^{kip2}$ and Rad9 during chemoprevention by turmeric and its derivatives especially in prostate cancer cell lines. Methods: Accordingly, in this study, we have examined the antitumor effect of several extracts of $C.$ $longa$ rhizomes by successive fractionation in clonogenic assays using highly metastatic PC-3M prostate cancer cell line. Results: A mixture of isopropyl alcohol: acetone: water: chloroform: and methanol extract of $C.$ $longa$ showed significant bioactivity. Further partition of this extract showed that bioactivity resides in the dichloromethane soluble fraction. Column chromatography of this fraction showed presence of biological activity only in ethyl acetate eluted fraction. HPLC, UV-Vis and Mass spectra studies showed presence three curcuminoids in this fraction besides few unidentified components. Conclusions: From these observations it was concluded that the ethyl acetate fraction showed not only inhibition of colony forming ability of PC-3M cells but also up-regulated cell cycle genes $p57^{kip2}$ and Rad9 and further reduced the migration and invasive ability of prostate cancer cells.