Chemopreventive Agents For Colon Cancer Research Articles

Novel insights into the biomolecular mechanism of action of 4′-geranyloxyferulic acid, a colon cancer chemopreventive agent

In this manuscript the biomolecular mechanism of action of the natural colon cancer chemopreventive agent 4′-geranyloxyferulic acid in cultured Caco-2 cells has been investigated. It was first demonstrated how the application of this phytochemical led to a time- and dose-dependent decrease of cell viability and in parallel to a massive generation of reactive oxygen species and induction of caspases 3 and 9, finally providing apoptosis. This event is accompanied by deep modifications in key pro-apoptotic targets like CD95, DR4 and 5, cytochrome c, Apaf-1, Bcl-2, and Bax. Such effects can explain the large apoptosis recorded in Caco-2 cells treated with 4′-geranyloxyferulic acid.

Anticancer Effect of Naringin on Human Colon Cancer (WiDr Cells): In Vitro Study

Naringin, a bioflavonoid naturally found in citrus species, has been exert as promising anticancer activities. However, naringin mechanism as anticancer still remain enigmatic. This study, WiDr cell lines as human colon cancer cell in vitro were used to evaluate anticancer effect of naringin. Naringin (10, 20, 40, 60, 80µg/mL) treated on WiDr cells to evaluate IC50 value by MTT assay, then continued with analyzed caspase-3 expressions (IC50, 2IC50) as apopotosis marker. This study reported that naringin inhibit the growth of WiDr cell with IC50 value is 63.14µg/mL. The caspase-3 expressions on 2IC50 is higher (74.66%) than IC50 (56.66%). These results indicate that naringin has properties of inhibting cell growth and inducing caspase-3 expressions on WiDr cells. It is a potential compound to be developed as a chemopreventive agent for colon cancer.

Piperlongumine targets NF-κB and its downstream signaling pathways to suppress tumor growth and metastatic potential in experimental colon cancer.

NF-κB is the principle transcription factor and plays the central role in orchestrating chronic inflammation by regulating levels of cytokines, chemokines and growth factors. Piperlongumine (PL), a major alkaloid in the fruit of Piper longum Linn. has gained worldwide attention for its anticancer properties, however, its mechanism of action in the chemoprevention of colon cancer has not been investigated yet. Therefore, the present study was designed to elucidate the underlying molecular mechanism of PL in preventing DMH/DSS induced experimental colon cancer in mice. In the current study well established DMH/DSS induced experimental colon cancer mouse model was used to demonstrate the chemopreventive potential of PL. The expression of NF-κB and its downstream target proteins was evaluated mainly through western blotting. In addition, CAM assay, immunohistochemical staining and gelatin zymography was used to show anti-angiogenic and anti-invasive potential of PL. Additionally, important tumor biomarkers such as TSA, LASA, LDH and IL-6 levels were also estimated. The results of current study showed that PL was capable to inhibit NF-κB activation as well as its nuclear translocation. PL administration to DMH/DSS treated mice also inhibited the NF-κB downstream signaling cascades such as including COX-2 pathway, JAK/STAT pathway, β-catenin, Notch signaling pathway, angiogenesis and epithelial to mesenchymal transition pathway. The findings of the present study have claimed PL as promising chemopreventive agent for colon cancer with pleiotropic action. The current study emphasizes that regular consumption of PL can be an effective approach in the prevention of colon cancer in humans.

Effects of polyisoprenoids from Avicennia lanata and Avicennia alba leaves on the gene expression of PI3K, Akt1, mTOR, P53, and EGFR in human colorectal adenocarcinoma WiDr cells

Background: Mangrove plants produce polyisoprenoid compounds. Polyisoprenoids have been proven to have anticancer properties. This study investigated the inhibitory activity of polyisoprenoids derived from the leaves of mangrove plants Avicennia alba and Avicennia lanata regarding the expression of PI3K, Akt1, mTOR, P53, and EGFR genes against human colorectal adenocarcinoma WiDr cells. Methods: Anticancer activity was tested through the MTT assay method performed on WiDr cells. The cell cycle and apoptosis were analysed by flow cytometry and double staining. Gene expression of PI3K, Akt1, mTOR, P53, and EGFR was observed using the RT-PCR method. Results: Cytotoxic activity against WiDr cells showed that the IC50 for A. alba and A. lanata was 258.14 ug/mL and 243.32 ug/mL, respectively. This observation indicated the possibility to develop moderate anticancer agents. The cell cycle showed that inhibition of A. alba and A. lanata occurred in the late phase of apoptosis S (10.60 and 10.51%) and G2-M1 (22.05 and 23.84%), which was higher than negative and positive control cells. Furthermore, the polyisoprenoids derived from A. alba and A. lanata leaves exhibited anticancer activity in WiDr cells through the downregulated gene expression of PI3K, Akt1, mTOR, and EGFR as well as the upregulated gene expression of P53. Conclusion: This study demonstrated that polyisoprenoids obtained from A. alba and A. lanata leaves are promising chemopreventive agents for colon cancer.

Effectiveness of theobromine on inhibition of 1,2-dimethylhydrazine-induced rat colon cancer by suppression of the Akt/GSK3β/β-catenin signaling pathway

• Theobromine, at both doses, prevented the formation of cancerous and precancerous lesions. • Theobromine, at both doses, enhanced the immunostaining of APC tumor suppressor. • Theobromine, at both doses, reduced the activation of Akt and expression of p-GSK3β and cyclin D1. • 200 mg/kg of theobromine reduced the mRNA and protein expression of β-catenin. This study aimed to investigate the effect of theobromine on dimethylhydrazine (DMH)-induced colon cancer. Male Wistar rats were divided into four groups and injected with saline (negative control) or 30 mg/kg DMH (other three groups) two times a week for 12 weeks. The negative control and DMH-treated control rats were treated with water and the other two groups with theobromine, at the dose of 100 or 200 mg/kg, two weeks before and during the period of injection. Both doses of theobromine reduced the volume and number of tumors, the number of aberrant crypts, and the expression of p-Akt, p-GSk3β, and cyclinD1, and also increased the expression of APC tumor suppressor. A significant reduction in the expression of β-catenin was observed in the rats treated with the high dose of theobromine. The results indicated that theobromine may be an effective chemopreventive agent for colon cancer by inhibition of the Akt/GSk3β/β-catenin pathway.

Effects of polyisoprenoids from Avicennia lanata and Avicennia alba leaves on the gene expression of PI3K, Akt1, mTOR, P53, and EGFR in human colorectal adenocarcinoma WiDr cells

Background:Mangrove plants produce polyisoprenoid compounds. Polyisoprenoids have been proven to have anticancer properties. This study investigated the inhibitory activity of polyisoprenoids derived from the leaves of mangrove plantsAvicennia albaandAvicennia lanataregarding the expression of PI3K, Akt1, mTOR, P53, and EGFR genes against human colorectal adenocarcinoma WiDr cells.Methods:Anticancer activity was tested through the MTT assay method performed on WiDr cells. The cell cycle and apoptosis were analysed by flow cytometry and double staining. Gene expression of PI3K, Akt1, mTOR, P53, and EGFR was observed using the RT-PCR method.Results:Cytotoxic activity against WiDr cells showed that the IC50 forA. albaandA. lanatawas 258.14 ug/mL and 243.32 ug/mL, respectively. This observation indicated the possibility to develop moderate anticancer agents. The cell cycle showed that inhibition ofA. albaandA. lanataoccurred in the late phase of apoptosis S (10.60 and 10.51%) and G2-M1 (22.05 and 23.84%), which was higher than negative and positive control cells. Furthermore, the polyisoprenoids derived fromA. albaandA. lanataleaves exhibited anticancer activity in WiDr cells through the downregulated gene expression of PI3K, Akt1, mTOR, and EGFR as well as the upregulated gene expression of P53.Conclusion:This study demonstrated that polyisoprenoids obtained fromA. albaandA. lanataleaves are promising chemopreventive agents for colon cancer.

Effects of polyisoprenoids from Avicennia lanata and Avicennia alba leaves on the gene expression of PI3K, Akt1, mTOR, P53, and EGFR in human colorectal adenocarcinoma WiDr cells

Background:Mangrove plants produce polyisoprenoid compounds. Polyisoprenoids have been proven to have anticancer properties. This study investigated the inhibitory activity of polyisoprenoids derived from the leaves of mangrove plantsAvicennia albaandAvicennia lanataregarding the expression of PI3K, Akt1, mTOR, P53, and EGFR genes against human colorectal adenocarcinoma WiDr cells.Methods:Anticancer activity was tested through the MTT assay method performed on WiDr cells. The cell cycle and apoptosis were analysed by flow cytometry and double staining. Gene expression of PI3K, Akt1, mTOR, P53, and EGFR was observed using the RT-PCR method.Results:Cytotoxic activity against WiDr cells showed that the IC50 forA. albaandA. lanatawas 258.14 ug/mL and 243.32 ug/mL, respectively. This observation indicated the possibility to develop moderate anticancer agents. The cell cycle showed that inhibition ofA. albaandA. lanataoccurred in the late phase of apoptosis S (10.60 and 10.51%) and G2-M1 (22.05 and 23.84%), which was higher than negative and positive control cells. Furthermore, the polyisoprenoids derived fromA. albaandA. lanataleaves exhibited anticancer activity in WiDr cells through the downregulated gene expression of PI3K, Akt1, mTOR, and EGFR as well as the upregulated gene expression of P53.Conclusion:This study demonstrated that polyisoprenoids obtained fromA. albaandA. lanataleaves are promising chemopreventive agents for colon cancer.

Polyisoprenoids from Avicennia marina induces on P13k, Akt1, Mammalian target of rapamycin, Egfr, and P53 Gene Expression Using Reverse Transcription-Polymerase Chain Reaction

BACKGROUND: According to the Global Cancer Observatory in 2018, Asia was the first to note the incidence of colon cancer, which was 51.8% of cases of colon cancer which ranked the top three in the number of causes of death in the world. Cancer is a disease characterized by uncontrolled cell growth. Potential natural ingredient developed as chemotherapeutic agents includes from mangrove leaves. Studies reporting on the pharmacological activity of polyisoprenoid from mangrove species are still limited, therefore, it is essential to achieve the prospects, potential, and mechanisms polyisoprenoid in mangroves as a natural ingredient of pharmaceutical and medication.
 AIM: The aim of the study was to investigate the inhibition activities of polyisoprenoids in mangrove plant Avicennia marina in WiDr cells induces on P13k, Akt1, mammalian target of rapamycin (mTOR), Egfr, and P53 gene expression using reverse transcription-polymerase chain reaction (RT-PCR).
 MATERIAL AND METHODS: The leaves of A. marina were dried and extracted with n-hexane followed by evaporation and freeze-drying. Polyisoprenoid contents were analyzed with two-dimensional thin-layer chromatography method. Cell viability was assessed with 3-(4,5-dimetiltiazol-2-il)-2,5-diphenyl tetrazolium bromide assay. The cycle cell was tested with flow cytometry method. The apoptotic test was determined with a double-staining method. The gene expression on P13k, Akt1, mTOR, Egfr, and P53 was analyzed by RT-PCR method.
 RESULTS: The results showed that 48 h cytotoxic activity of polyisoprenoids against WiDr cells and 5-Fu (positive control) had IC50 values, 295.25 μg/mL and 17.43 μg/mL. Cell cycle analysis depicted that the inhibition of polyisoprenoid occurred in the G0-G1 phase and 5-Fu in S phase. Polyisoprenoid and 5-Fu had the same mechanism in the early apoptotic phase. RT-PCR revealed that polyisoprenoids downregulated the P13k, Akt1, mTOR, and Egfr gene expression, and however, upregulated P53 gene expression.
 CONCLUSION: The present study confirmed that polyisoprenoids from A. marina leaves showing as chemopreventive agents for colon cancer.

Effects of polyisoprenoids from Avicennia lanata and Avicennia alba leaves on the gene expression of PI3K, Akt1, mTOR, P53, and EGFR in human colorectal adenocarcinoma WiDr cells using reverse transcription-PCR

Background:Mangrove plants produce a polyisoprenoid compound. Polyisoprenoids have been proven to have anticancer properties. This study investigated the inhibitory activity of polyisoprenoids derived from the leaves of mangrove plantsAvicennia albaandAvicennia lanataregarding the expression of PI3K, Akt1, mTOR, P53, and EGFR genes against human colorectal adenocarcinoma WiDr cells.Methods:Anticancer activity was tested through the MTT assay method performed on WiDr cells. The inhibited cell cycle and apoptosis were analysed by flow cytometry and double staining. Gene expression of PI3K, Akt1, mTOR, P53, and EGFR was observed using the RT-PCR method.Results:Cytotoxic activity against WiDr cells showed that the IC50 forA. albaandA. lanatawas 258.14 ug/mL and 243.32 ug/mL, respectively. This indicated that their classification as anticancer agents was moderate. The cell cycle showed that inhibition ofA. albaandA. lanataoccurred in the late phase of apoptosis S (10.60 and 10.51%) and G2-M1 (22.05 and 23.84%), which was higher than negative and positive control cells. Furthermore, the polyisoprenoids derived fromA. albaandA. lanataleaves exhibited anticancer activity in WiDr cells through the downregulated gene expression of PI3K, Akt1, mTOR, and EGFR as well as the upregulated gene expression of P53.Conclusion:This study demonstrated that polyisoprenoids obtained fromA. albaandA. lanataleaves are promising chemopreventive agents for colon cancer.

Piperlongumine, a piper alkaloid targets Ras/PI3K/Akt/mTOR signaling axis to inhibit tumor cell growth and proliferation in DMH/DSS induced experimental colon cancer

Colorectal cancer (CRC) is the most common carcinoma of the digestive tract. The slow growing nature of CRC offers a great opportunity for prevention strategies. The concept of chemoprevention of colorectal cancer using plant derived natural products is gaining substantial attention because it is an inherently safe and cost-effective alternative to conventional cancer therapies. Piperlongumine (PL), a natural alkaloid present in Piper longum Linn has been reported to exhibit notable anticancer effects in various in vitro studies. Nonetheless, the chemopreventive potential of PL has not been studied in experimentally induced colon cancer yet. Ras/PI3K/Akt/mTOR signaling axis plays a central role in promoting tumor cell growth, proliferation and survival by inhibiting apoptosis. In the present study, we demonstrated, for the first time, the chemopreventive effects of PL in DMH + DSS induced colon carcinogenesis animal model. We showed that PL displayed potent antineoplastic activity against colon cancer cell growth by targeting Ras proteins and PI3K/Akt signaling cascade. PL mediated inhibition of tumor cell growth was associated with inhibition of Ras protein levels and its preferred companion protein PI3K levels that led to suppressed activity of Akt/NF-κB, c-Myc and cyclin D1. It was also found that PL arrested the cell cycle progression at G2/M phase and induced mitochondrial apoptotic pathway by downregulating Bcl-2 levels. Furthermore, the results of liver and kidney toxicity suggested that PL exhibit no toxicity in animals. Our results suggest that PL may be an effective chemopreventive agent for colon cancer.

Clinically Relevant Anti-Inflammatory Agents for Chemoprevention of Colorectal Cancer: New Perspectives.

Substantial efforts are underway for prevention of early stages or recurrence of colorectal cancers (CRC) or new polyp formation by chemoprevention strategies. Several epidemiological, clinical and preclinical studies to date have supported the chemopreventive potentials of several targeted drug classes including non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin, naproxen, sulindac, celecoxib, and licofelone), statins and other natural agents—both individually, and in combinations. Most preclinical trials although were efficacious, only few agents entered clinical trials and have been proven to be potential chemopreventive agents for colon cancer. However, there are limitations for these agents that hinder their approval by the food and drug administration for chemoprevention use in high-risk individuals and in patients with early stages of CRC. In this review, we update the recent advancement in pre-clinical and clinical development of selected anti-inflammatory agents (aspirin, naproxen, sulindac, celecoxib, and licofelone) and their combinations for further development as novel colon cancer chemopreventive drugs. We provide further new perspectives from this old research, and insights into precision medicine strategies to overcome unwanted side-effects and overcoming strategies for colon cancer chemoprevention.

THE INHIBITION OF POLYISOPRENOIDS FROM NYPA FRUTICANS LEAVES ON CYCLOOXYGENASE 2 EXPRESSION OF WIDR COLON CANCER CELLS

Objective: The objective of the study was to investigate the inhibitory activity of polyisoprenoids from Nypa fruticans leaves on the expression of cyclooxygenase 2 (COX-2) against colon cancer cells.Methods: Anticancer activity performed was tested by dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method on colon cancer cell WiDr. The expression of COX-2 was observed by the immunocytochemistry method.Result: Polyisoprenoids from N. fruticans leaves exhibit anticancer activity on WiDr cells through inhibition of COX-2 expression with IC50 180.186±7.16 μg/ml.Conclusions: This study showed that polyisoprenoids from N. fruticans leaves promise chemopreventive agents for colon cancer through COX-2 inhibition.

Wasabi 6-(methylsulfinyl)hexyl isothiocyanate induces apoptosis in human colorectal cancer cells through p53-independent mitochondrial dysfunction pathway.

6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC), a major bioactive compound in Wasabi [Wasabia japonica (Miq.) Matsum.], has revealed the inhibitory effect on colon carcinogenesis in rat cancer model although the underlying mechanism is unclear. In this study, we used two types of human colorectal cancer cells (HCT116 p53+/+ and HCT116 p53-/- ) to investigate the anticancer activity and molecular mechanisms of 6-MSITC. Interestingly, 6-MSITC inhibited the cell proliferation in both types of cells with similar IC50 value although a light increase in the phosphorylation and accumulation of P53 protein was observed in HCT116 p53+/+ cells at 24 h after treatment. In addition, 6-MSITC increased the ratio of proapoptotic cells in both types of cells with the same fashion in a p53-independent manner. The data from mitochondrial analysis revealed that 6-MSITC enhanced the ratio of proapoptotic B-cell lymphoma-2-associated X protein/antiapoptotic myeloid cell leukemia 1, and sequentially caused mitochondrial membrane potential (ΔΨm ) loss, cytochrome c release, and caspase-3 activation in both types of cells. Taken together, Wasabi 6-MSITC induced apoptosis of human colorectal cancer cells in p53-independent mitochondrial dysfunction pathway. These findings suggest that 6-MSITC might be a potential agent for colon cancer chemoprevention although with p53 mutation. © 2018 BioFactors, 2018.

The effect ofPerilla frutescensleaf on 1, 2-dimethylhydrazine-induced initiation of colon carcinogenesis in rats

In this study, the chemopreventive properties of Perilla frutescens leaf extract (PLE) on rat colon carcinogenesis were investigated during initiation and postinitiation stages. Rats were fed orally by 50 and 500 mg/kg bw of PLE continuously from 1 week before subcutaneously injection of 1,2-dimethylhydrazine (DMH) until the end of experiment. PLE administration reduced the aberrant crypt foci (ACF) number in DMH-treated rats through the inhibition of hepatic cytochrome P4502E1 (CYP2E1) and bacterial β-glucuronidase activity in the colonic lumen. These events led to the reduction of DNA methylation in colonic epithelial cells. For the postinitiation model, rats were injected (s.c.) with DMH, followed by PLE administration until the end of experiment. PLE administration also reduced the ACF number in DMH-induced rats, resulting from apoptosis induction and reduction of proliferation in colon crypt cells. These studies demonstrated that perilla leaf could inhibit ACF formation and progression in DMH-initiated colon carcinogenesis in rats. Practical applications This study revealed the inhibitory effect of PLE on chemical-induced colon carcinogenesis in rats. Altogether, our data supported that PLE acts as a chemopreventive agent for colon cancer. Thus, PLE might be developed as food supplement or functional tea for colon cancer prevention.

Antrodia camphorata inhibits metastasis and epithelial-to-mesenchymal transition via the modulation of claudin-1 and Wnt/β-catenin signaling pathways in human colon cancer cells

Ethnopharmacological relevanceAntrodia camphorata (AC) is a well known traditional Chinese medicinal mushroom in Taiwan, has been used to treat various diseases including cancer. Materials and methodsIn this study, we investigated the anti-metastatic and anti-EMT properties of a fermented culture broth of AC in human colon SW480claudin−1- and metastatic SW620claudin−1+ cancer cells in vitro. ResultsAC down-regulates claudin-1 and inhibits the proliferation and colony-formation abilities of both SW620claudin−1+ and SW480claudin−1- cells. In highly metastatic SW620claudin−1+ cells, non-cytotoxic concentrations of AC significantly inhibited migration/invasion, accompanied by the down-regulation of MMP-2 and MMP-9 proteins. AC decreased nuclear translocation of Wnt/β-catenin through a GSK3β-dependent pathway. AC consistently inhibited EMT by up-regulating the epithelial and downregulating the mesenchymal marker proteins. In SW480claudin−1- cells, AC suppressed migration/invasion potentially through the inhibition of the PI3K/AKT/NFκB signaling pathways without altering the expression levels of β-catenin and GSK3β proteins. ConclusionAltogether, this study demonstrates the anti-metastatic and anti-EMT activities of AC, which may contribute to the development of a chemopreventive agent for colon cancer.

Strawberry-Tree Honey Induces Growth Inhibition of Human Colon Cancer Cells and Increases ROS Generation: A Comparison with Manuka Honey.

Honey is a natural product known to modulate several biological activities including cancer. The aim of the present study was to examine the phytochemical content and the antioxidant activity of Strawberry tree (Arbutus unedo) honey (STH) and its cytotoxic properties against human colon adenocarcinoma (HCT-116) and metastatic (LoVo) cell lines in comparison with Manuka (Leptospermum scoparium) honey (MH). Several unifloral STH and MH were analyzed for their phenolic, flavonoid, amino acid and protein contents, as well as their radical scavenging activities. STH from the Berchidda area showed the highest amount of phenolic, flavonoid, amino acid and protein content, and antioxidant capacity compared to MH. Both STH and MH induced cytotoxicity and cell death in a dose- and time-dependent manner in HCT-116 and LoVo cells, with less toxicity on non-cancer cells. Compared to MH, STH showed more effect at lower concentrations on HCT-116 and LoVo cells. In addition, both honeys increased intracellular reactive oxygen species (ROS) generation. In HCT-116 cells, STH and MH induced similar ROS production but in LoVo cells STH induced a higher percentage of ROS compared to MH. Our results indicate that STH and MH can induce cell growth inhibition and ROS generation in colon adenocarcinoma and metastatic cells, which could be due to the presence of phytochemicals with antioxidant properties. These preliminary results are interesting and suggest a potential chemopreventive action which could be useful for further studies in order to develop chemopreventive agents for colon cancer.

Stereoisomers of Astaxanthin Inhibit Human Colon Cancer Cell Growth by Inducing G2/M Cell Cycle Arrest and Apoptosis.

Astaxanthin (AST) is a xanthophyll carotenoid with potential protective effects against carcinogenesis. Different stereoisomers of AST (ASTs) exist in a variety of food sources. Due to limited information on the bioactivities of ASTs, the present study investigated the inhibitory effects of ASTs on HCT116 and HT29 human colon cancer cells. ASTs investigated herein included 3S,3'S (S) from Haematococcus pluvialis, 3R,3'R (R) from Phaffia rhodozyma, and a statistical mixture (S: meso: R = 1:2:1) (M) from synthetic AST. Cell viability assay showed that ASTs all inhibited colon cancer cell growth in a time-dependent (24-72 h) and dose-dependent (4-16 μM) manner, and there was no significant difference among the IC50 values of ASTs (p > 0.05). Flow cytometry analysis indicated that ASTs induced G2/M cell cycle arrest and cellular apoptosis in cancer cells. The cell cycle arrest caused by ASTs was associated with increases in the expression levels of p21Cip1/Waf1, p27, and p53, as well as decreases in the levels of CDK4 and CDK6. Meanwhile, the apoptosis induced by ASTs was confirmed by activation of caspase-3 and PARP in the cancer cells. The results indicated that hydroxyl (OH) at C3 and C3' of terminal ring structure might not be the major factor that affects the anticancer activity of AST. This study revealed important information on the inhibitory effects of ASTs on human colon cancer cells, which provided a basis for using ASTs as chemopreventive agents for colon cancer.

Valdecoxib Recovers the Lipid Composition, Order and Dynamics in Colon Cancer Cell Lines Independent of COX-2 Expression: An ATR-FTIR Spectroscopy Study.

Prostanoids play an important role in a variety of physiological and pathophysiological processes including inflammation and cancer. The rate-limiting step in the prostanoid biosynthesis pathway is catalyzed by cyclooxygenases (COXs). Aberrant expression of the inducible isoform COX-2 plays a significant role in colon cancer initiation and progression. In this study, we have hypothesized that COX-2 specific inhibitors such as Valdecoxib (VLX), being highly hydrophobic, may alter biophysical properties of cellular lipids. In this study, COX-2 expressing (HT29) and COX-2 non-expressing (SW620) colon cancer cell lines were treated with VLX and examined using attenuated total reflection infrared spectroscopy. The results revealed that VLX treatment decreased lipid fluidity in the cells irrespective of COX-2 expression status and affected order parameters of the lipids in both cell lines. Cluster analysis also indicated that the spectral differences between the two cell lines are profound and could be successfully differentiated. Valdecoxib treatment could enhance the composition, order and dynamics of the lipids of colon cancer cells independently of its COX-2 inhibitory mechanism. Valdecoxib has therapeutic effects upon colon cancer, therefore it can be used as an adjuvant and/or chemopreventive agent for colon cancer.

Abstract 2601: Gingerol aspirinate derivatives as novel chemopreventive agents for colon cancer

Abstract Regular aspirin use has been convincingly shown to reduce the risk of colorectal cancer. However, long-term use of aspirin leads to gastrotoxicity. Herein, we designed and synthesized a novel class of gingerol- and shogaol-based aspirin prodrugs to simultaneously release aspirin and gingerol or shogaol to attenuate the side effects caused by aspirin. Prodrug GAS exerted enhanced anticancer activities, which are better than a physical mixture of aspirin and 6-gingerol as well as each individual. In addition, GAS eliminated the gastric toxicity induced by aspirin in mice. Metabolism of GAS in mice showed that the majority of GAS is decomposed to release 6-gingerol and aspirin or salicylic acid either in the intestine or after absorption. Mechanistic studies demonstrate GAS could dose-dependently inhibit COX pathway. These findings highlighted the improved anticancer properties of gingerol-based aspirin prodrugs. GAS may represent novel and safe alternatives of aspirin for the purpose of daily use in the future. Citation Format: Yingdong Zhu, Fang Wang, Yantao Zhao, Pei Wang, Shengmin Sang. Gingerol aspirinate derivatives as novel chemopreventive agents for colon cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2601.

Goniothalamin prevents the development of chemically induced and spontaneous colitis in rodents and induces apoptosis in the HT-29 human colon tumor cell line

Colon cancer is the third most incident type of cancer worldwide. One of the most important risk factors for colon cancer development are inflammatory bowel diseases (IBD), thus therapies focusing on IBD treatment have great potential to be used in cancer prevention. Nature has been a source of new therapeutic and preventive agents and the racemic form of the styryl-lactone goniothalamin (GTN) has been shown to be a promising antiproliferative agent, with gastroprotective, antinociceptive and anti-inflammatory effects. As inflammation is a well-known tumor promoter, the major goal of this study was to evaluate the therapeutic and preventive potentials of GTN on chemically induced and spontaneous colitis, as well as the cytotoxic effects of GTN on a human colon tumor cell line (HT-29). GTN treatments inhibited TNBS-induced acute and chronic colitis development in Wistar rats, reducing myeloperoxidase levels and inflammatory cells infiltration in the mucosa. In spontaneous-colitis using IL-10 deficient mice (C57BL/6 background), GTN prevented colitis development through downregulation of TNF-α, upregulation of SIRT-1 and inhibition of proliferation (PCNA index), without signs of toxicity after three months of treatment. In HT-29 cells, treatment with 10μM of GTN induced apoptosis by increasing BAX/BCL2, p-JNK1/JNK1, p-P38/P38 ratios as well as through ROS generation. Caspase 8, 9 and 3 activation also occurred, suggesting caspase-dependent apoptotic pathway, culminating in PARP-1 cleavage. Together with previous data, these results show the importance of GTN as a pro-apoptotic, preventive and therapeutic agent for IBD and highlight its potential as a chemopreventive agent for colon cancer.