Inhibits Colon Cancer Cell Growth Research Articles

5-Demethylnobiletin more potently inhibits colon cancer cell growth than nobiletin in vitro and in vivo

Nobiletin (NOB) and 5-demethylnobiletin (DMNB) are unique polymethoxyflavones (PMFs) found in citrus peel that exhibit anti-tumoral action in several cancer cell models. The differences between NOB and DMNB with respect to their anti-proliferative potencies and underlying molecular mechanism were compared in this contribution. The results of the cell viability assay suggested that DMNB resulted in more enhanced growth inhibitory effects than NOB in human colon cancer cell lines (HCT-116, HT-29 and COLO 205). Flow cytometry data found that DMNB inhibited proliferation in COLO 205 cells by predominantly inducing apoptosis. A xenograft mouse model further demonstrated that DMNB exhibited more preferential anti-colon cancer effects than NOB via its ability to induce p53-regulated cell death signaling (apoptosis and autophagy) and inhibit key cellular markers associated with inflammation and angiogenesis. Taken together, our findings provide evidence for the first time that natural bioactive DMNB might serve as a promising polymethoxyflavone for chemoprevention of colorectal cancer.

Novel Polyphenols That Inhibit Colon Cancer Cell Growth Affecting Cancer Cell Metabolism

New series of polyphenols with a hydrophilic galloyl-based head and a hydrophobic N-acyl tail, linked through a serinol moiety, have been synthesized and tested against colon cancer cell growth. Our structure activity relationship studies revealed that galloyl moieties are essential for growth inhibition. Moreover, the length of the N-acyl chain is crucial for the activity. Introduction of a (Z) double bond in the acyl chain increased the anticancer properties. Our findings demonstrate that 16, the most potent compound within this series, has inhibitory effects on colon cancer cell growth and metabolism (glycolysis and mitochondrial respiration) at the same time that it activates 5'AMP-activated kinase (AMPK) and induces apoptotic cell death. Based on these results, we propose that 16 might reprogram colon cancer cell metabolism through AMPK activation. This might lead to alterations on cancer cell bioenergy compromising cancer cell viability. Importantly, these antiproliferative and proapoptotic effects are selective for cancer cells. Accordingly, these results indicate that 16, with an unsaturated C18 chain, might be a useful prototype for the development of novel colon cancer cell growth inhibitors affecting cell metabolism.

NPTX1 inhibits colon cancer cell proliferation through down-regulating cyclin A2 and CDK2 expression.

Colon cancer is the third most common malignancy and one of the leading causes of cancer-associated mortality worldwide. Neuronal pentraxin 1 (NPTX1) is associated with tumor progression in some types of tumors. However, its expression and role in colon cancer has not been yet reported. Here we observed that NPTX1 was down-regulated in colon cancer. Additionally, we explored the functional significance of NPTX1 in colon cancer. We found that over-expression of NPTX1 inhibited colon cancer cell growth by performing MTT, colony formation, Edu corporation assays, and cell cycle analysis. In vivo mouse experiments also confirmed the anti-proliferative role of NPTX1 in colon cancer. Further mechanistic study showed that over-expression of NPTX1 inhibited the expression of cyclin A2 and CDK2 in colon cancer cells, thereby regulating the Rb-E2F signaling. In summary, these findings reveal that NPTX1 suppress the colon cancer cell growth and might serve as a useful potential target for treatment of colon cancer.

XRCC5 cooperates with p300 to promote cyclooxygenase-2 expression and tumor growth in colon cancers.

Cyclooxygenase (COX) is the rate-limiting enzyme in prostaglandins (PGs) biosynthesis. Previous studies indicate that COX-2, one of the isoforms of COX, is highly expressed in colon cancers and plays a key role in colon cancer carcinogenesis. Thus, searching for novel transcription factors regulating COX-2 expression will facilitate drug development for colon cancer. In this study, we identified XRCC5 as a binding protein of the COX-2 gene promoter in colon cancer cells with streptavidin-agarose pulldown assay and mass spectrometry analysis, and found that XRCC5 promoted colon cancer growth through modulation of COX-2 signaling. Knockdown of XRCC5 by siRNAs inhibited the growth of colon cancer cells in vitro and of tumor xenografts in a mouse model in vivo by suppressing COX-2 promoter activity and COX-2 protein expression. Conversely, overexpression of XRCC5 promoted the growth of colon cancer cells by activating COX-2 promoter and increasing COX-2 protein expression. Moreover, the role of p300 (a transcription co-activator) in acetylating XRCC5 to co-regulate COX-2 expression was also evaluated. Immunofluorescence assay and confocal microscopy showed that XRCC5 and p300 proteins were co-located in the nucleus of colon cancer cells. Co-immunoprecipitation assay also proved the interaction between XRCC5 and p300 in nuclear proteins of colon cancer cells. Cell viability assay indicated that the overexpression of wild-type p300, but not its histone acetyltransferase (HAT) domain deletion mutant, increased XRCC5 acetylation, thereby up-regulated COX-2 expression and promoted the growth of colon cancer cells. In contrast, suppression of p300 by a p300 HAT-specific inhibitor (C646) inhibited colon cancer cell growth by suppressing COX-2 expression. Taken together, our results demonstrated that XRCC5 promoted colon cancer growth by cooperating with p300 to regulate COX-2 expression, and suggested that the XRCC5/p300/COX-2 signaling pathway was a potential target in the treatment of colon cancers.

MicroRNA-1299 is a negative regulator of STAT3 in colon cancer.

Signal transducers and activators of transcription (STAT) is a family of transcription factors which regulate cell proliferation, differentiation, apoptosis, metastasis, immune and inflammatory responses, and angiogenesis. STAT3 is a latent cytoplasmic transcription factor that belongs to STATs. STAT3 has been reported be regulates genes involved with cellular growth, proliferation and metastasis. Worldwide, colon cancer is one of the leading causes of cancer-related deaths. Cumulative evidence has established that STAT3 is essential for colon cancer progression to advanced malignancy. In our study, we showed that microRNA-1299 (miR-1299) was closely related to the TNM stage of colon cancer, and that the expression of miR-1299 was negatively correlated with the expression of STAT3 in colon cancer which means that miR-1299 can be a negative regulator of STAT3 in colon cancer. A total of 60 cases of different grades of colon samples were used to detect the expression of miR-1299. Results showed that miR-1299 was significantly lower in high-grade colons both in mRNA and protein levels. Furthermore, Overall survival (OS) in patients with low miR-1299 is shorter than 25.6 months, as compared with an OS of 28.4 months in patients with high level of miR-1299. We also confirmed that the overexpression of miR-1299 can not only downregulate the STAT3 pathway, but also inhibited colon cancer cell growth. Our findings could provide new insights into the molecular therapeutic of colon cancer.

S-Allylmercaptocysteine induces G2/M phase arrest and apoptosis via ROS-mediated p38 and JNK signaling pathway in human colon cancer cells in vitro and in vivo

SAMC inhibits colon cancer cell growth through the reactive oxygen species-dependent pathway.

Anti-cancer Effects of MW-03, a Novel Indole Compound, by Inducing 15-Hydroxyprostaglandin Dehydrogenase and Cellular Growth Inhibition in the LS174T Human Colon Cancer Cell Line.

Increases in the expression of prostaglandin E2 (PGE2) are widely known to be involved in aberrant growth in the early stage of colon cancer development. We herein demonstrated that the novel indole compound MW-03 reduced PGE2-induced cAMP formation by catalization to an inactive metabolite by inducing 15-hydroxyprostaglandin dehydrogenase through the activation of peroxisome proliferator-activated receptor-γ. MW-03 also inhibited colon cancer cell growth by arresting the cell cycle at the S phase. Although the target of MW-03 for cell cycle inhibition has not yet been identified, these dual anti-cancer effects of MW-03 itself and/or its leading compound(s) on colon cancer cells may reduce colon cancer development and, thus, have potential as a novel treatment for the early stage of this disease.

8‐C‐(E‐phenylethenyl)quercetin from onion/beef soup induces autophagic cell death in colon cancer cells through ERK activation

Quercetin, a flavonoid, widely distributed in edible fruits and vegetables, was reported to effectively inhibit 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP) formation in a food model (roast beef patties) with itself being converted into a novel compound 8-C-(E-phenylethenyl)quercetin (8-CEPQ). Here we investigated whether 8-CEPQ could be formed in a real food system, and tested its anticancer activity in human colon cancer cell lines. LC-MS was applied for the determination of 8-CEPQ formation in onion/beef soup. Anticancer activity of 8-CEPQ was evaluated by using cell viability assay and flow cytometry. Results showed that 8-CEPQ suppressed proliferationand caused G2 phase arrest in colon cancer cells. Based on immunofluorescent staining assay, western blot assay, and RNA knockdown data, we found that 8-CEPQ did not cause apoptotic cell death. Instead, it induced autophagic cell death. Moreover, treatment with 8-CEPQ induced phosphorylation of extracellular signal-regulated kinase (ERK). Inhibition of ERK phosphorylation by the mitogen-activated protein kinasekinase (MEK)/ERK inhibitor U0126 attenuated 8-CEPQ-induced autophagy and reversed 8-CEPQ-mediated cell growth inhibition. Our results demonstrate that 8-CEPQ, a novel quercetin derivative, could be formed in onion/beef soup. 8-CEPQ inhibited colon cancer cell growth by inducing autophagic cell death through ERK activation.

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.

Abrin P2 suppresses proliferation and induces apoptosis of colon cancer cells via mitochondrial membrane depolarization and caspase activation.

To explore the cytotoxic mechanism of abrin P2 on human colon cancer HCT-8 cells, abrin P2 was isolated from the seed of Abrus precatorius L. It was found that abrin P2 exhibited cytotoxicity toward 12 different human cancer cell lines. Our results demonstrated that abrin P2 suppressed the proliferation of human colon cancer cells (HCT-8 cells) and induced cell cycle arrest at the S and G2/M phases. The mechanism by which abrin P2 inhibited cell proliferation was via the down-regulation of cyclin B1, proliferating cell nuclear antigen and Ki67, as well as the up-regulation of P21. In addition, abrin P2 induced a dose- and time-dependent increase in the rate of HCT-8 cell apoptosis. Treatment with both Z-VAD-FMK, a broad-spectrum caspase inhibitor, and abrin P2 demonstrated that abrin P2 induced HCT-8 cell apoptosis via the activation of caspases. Together, our results revealed that abrin P2-induced apoptosis in HCT-8 cells was associated with the activation of caspases-3/-8/-9, the reduction in the Bcl-2/Bax ratio, the loss of mitochondrial membrane potential, and the increase in cytochrome c release. We further showed that abrin P2 administration effectively suppressed the growth of colon cancer xenografts in nude mice. This is the first report that abrin P2 effectively inhibits colon cancer cell growth in vivo and in vitro by suppressing proliferation and inducing apoptosis.

Knockdown of delta-5-desaturase promotes the anti-cancer activity of dihomo-γ-linolenic acid and enhances the efficacy of chemotherapy in colon cancer cells expressing COX-2

Cyclooxygenase (COX), commonly overexpressed in cancer cells, is a major lipid peroxidizing enzyme that metabolizes polyunsaturated fatty acids (ω-3s and ω-6s). The COX-catalyzed free radical peroxidation of arachidonic acid (ω-6) can produce deleterious metabolites (e.g. 2-series prostaglandins) that are implicated in cancer development. Thus, COX inhibition has been intensively investigated as a complementary therapeutic strategy for cancer. However, our previous study has demonstrated that a free radical-derived byproduct (8-hydroxyoctanoic acid) formed from COX-catalyzed peroxidation of dihomo-γ-linolenic acid (DGLA, the precursor of arachidonic acid) can inhibit colon cancer cell growth. We thus hypothesize that the commonly overexpressed COX in cancer (~90% of colon cancer patients) can be taken advantage to suppress cell growth by knocking down delta-5-desaturase (D5D, a key enzyme that converts DGLA to arachidonic acid). In addition, D5D knockdown along with DGLA supplement may enhance the efficacy of chemotherapeutic drugs. After knocking down D5D in HCA-7 colony 29 cells and HT-29 cells (human colon cancer cell lines with high and low COX levels, respectively), the antitumor activity of DGLA was significantly enhanced along with the formation of a threshold range (~0.5–1.0μM) of 8-hydroxyoctanoic acid. In contrast, DGLA treatment did not inhibit cell growth when D5D was not knocked down and only limited amount of 8-hydroxyoctanoic acid was formed. D5D knockdown along with DGLA treatment also enhanced the cytotoxicities of various chemotherapeutic drugs, including 5-fluorouracil, regorafenib, and irinotecan, potentially through the activation of pro-apoptotic proteins, e.g. p53 and caspase 9. For the first time, we have demonstrated that the overexpressed COX in cancer cells can be utilized in suppressing cancer cell growth. This finding may provide a new option besides COX inhibition to optimize cancer therapy. The outcome of this translational research will guide us to develop a novel ω-6-based diet-care strategy in combination with current chemotherapy for colon cancer prevention and treatment.

Development and therapeutic potential of NOSH‐NSAIDs: A new class of anti‐inflammatory pharmaceuticals

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are mainly used to treat pain, reduce fever and inflammation; some also have utility as anti‐platelet agents. There is also a large body of data supporting the notion that NSAIDs are important for cancer prevention. However, their long‐term use is problematic on two accounts: (1) suboptimal efficacy, which is less than 50% and (2) side effects including gastrointestinal, cardiovascular, and renal, which precludes their widespread use. In our search for a “better NSAID”, we developed NOSH‐NSAIDs. These are regular NSAIDs such as aspirin, naproxen, sulindac and others to which nitric oxide (NO) and hydrogen sulfide (H2S) releasing moieties have been covalently attached. Both NO and H2S are gaseous signaling molecules of biological importance. The rational for incorporating these gaseous mediators into NSAID molecules was based on the observations that NO and H2S have some of the same properties as prostaglandins within the gastric mucosa, thus modulating some components of the local mucosal defense systems which should lead to reduced gastrointestinal toxicity and also should embark enhanced cardiovascular and renal safety profiles because NO and H2S have protective roles in the cardiovascular and renal systems. To date we have reported on the synthesis and some general characterizations of three such compounds. NOSH‐aspirin (NBS‐1120), NOSH‐naproxen (AVT‐219), and NOSH‐sulindac (AVT‐18A) have enhanced GI profiles yet they retain all the basic pharmacological activities of their respective native NSAID. Furthermore, we have also reported that these compounds are orders of magnitude more potent than their corresponding NSAID in inhibiting the growth of adenomatous, epithelial, and lymphocytic cancer cell lines, thus demonstrating a generalized property that was tissue‐type independent. In vivo, NBS‐1120 was shown to have chemo‐preventive properties that were superior to aspirin and AVT‐219 was shown to have chemotherapeutic properties. Of interest is also the observation that NBS‐1120 showed synergistic activity with 5‐flurouracil, an established chemotherapeutic agent, in inhibiting colon cancer cell growth. Encouraged by our initial observations, we have formed a company, Avicenna Pharmaceuticals, Inc., around this technology and have forged a path towards an IND application and phase‐1 clinical trials, hopefully to bring these compounds into the clinic.

Epigenetic drift towards histone modifications regulates CAV1 gene expression in colon cancer

BackgroundCaveolin-1 (CAV1) is an important structural component of cellular caveolae involved in cell signaling. CAV1 gene on/off regulatory mechanism in multiple diseases, including cancer is not clearly understood. The tumor suppressor versus oncogene paradox of CAV1 during tumor development tempted us to investigate the role for the epigenetic drift of CAV1 gene regulation. MethodsWe have analyzed CAV1 gene expression and associated epigenetic marks (DNA methylation and histone 3 modifications) in the CAV1 promoter in two colon cancer cell lines, under treatment with well established epigenetic modulators, AZA, SAM, TSA and SFN at varying concentrations. CAV1 gene promoter DNA methylation and histone modifications were analyzed by DNA methylation specific PCR, bisulphite modification of DNA and ChIP analyses following PCR respectively. ResultsEctopic expression of CAV1 by epigenetic modulators inhibits colon cancer cell growth. CAV1 promoter DNA remains unmethylated before and after treatment with epigenetic modulators, which confirmed that DNA methylation is not the regulator of CAV1 expression in colon cancer. There was enrichment of H3K4me3 and H3K9AcS10P and depletion of H3K9me3 modifications around the CAV1 promoter. ConclusionsOur data provides novel insight into the regulation of CAV1 gene by histone H3 modifications and enhance the amplitude of the cancer epigenome.

In vitro Antitumour Activity of Tomato-Extracted Carotenoids on Human Colorectal Carcinoma

The aim of this research was to establish whether all-trans lycopene extracted from fresh and frozen tomatoes is able to inhibit the in vitro proliferation of colon cancer cells, to trigger apoptosis by reactive oxygen species modulation and to reveal its influence on NF-kβ signalling, through the p65 transcription factor and expression of two TNF receptors: GITR and CD27. The carotenoid extracts containing all-trans lycopene were obtained from fresh (E1) and frozen/thawed (E2) tomatoes (Lycopersicon esculentum Mill.), hybrid ‘Menhir’ F1. DLD-1 and HT-29 human colon adenocarcinoma cell lines were co-cultivated with the two extracts and cytotoxicity, apoptosis, antioxidant activity, reactive oxygen species as well as modulation of NF-kβ signalling pathway were assessed. Tomato extracts E1 and E2 were able to inhibit colon cancer cell growth in vitro. E2 contained a higher proportion of all-trans lycopene and displayed superior cytotoxicity and a better apoptosis inducing capacity. The two extracts proved antioxidant activity against DPPH radicals and were able to scavenge the reactive oxygen species in the treated tumour cells. This study also showed that lycopene acts mainly through p65 protein and moderately by TNF receptors GITR and CD27 to deactivate the NF-kβ signalling pathway involved in cancer cell proliferation.

Combination of tolfenamic acid and curcumin induces colon cancer cell growth inhibition through modulating specific transcription factors and reactive oxygen species.

Curcumin (Cur) has been extensively studied in several types of malignancies including colorectal cancer (CRC); however its clinical application is greatly affected by low bioavailability. Several strategies to improve the therapeutic response of Cur are being pursued, including its combination with small molecules and drugs. We investigated the therapeutic efficacy of Cur in combination with the small molecule tolfenamic acid (TA) in CRC cell lines. TA has been shown to inhibit the growth of human cancer cells in vitro and in vivo, via targeting the transcription factor specificity protein1 (Sp1) and suppressing survivin expression. CRC cell lines HCT116 and HT29 were treated with TA and/or Cur and cell viability was measured 24–72 hours post-treatment. While both agents caused a steady reduction in cell viability, following a clear dose/time-dependent response, the combination of TA+Cur showed higher growth inhibition when compared to either single agent. Effects on apoptosis were determined using flow cytometry (JC-1 staining to measure mitochondrial membrane potential), Western blot analysis (c-PARP expression) and caspase 3/7 activity. Reactive oxygen species (ROS) levels were measured by flow cytometry and the translocation of NF-kB into the nucleus was determined using immunofluorescence. Results showed that apoptotic markers and ROS activity were significantly upregulated following combination treatment, when compared to the individual agents. This was accompanied by decreased expression of Sp1, survivin and NF-kB translocation. The combination of TA+Cur was more effective in HCT116 cells than HT29 cells. These results demonstrate that TA may enhance the anti-proliferative efficacy of Cur in CRC cells.

Sulindac sulfide inhibits colon cancer cell growth and downregulates specificity protein transcription factors

BackgroundSpecificity protein (Sp) transcription factors play pivotal roles in maintaining the phenotypes of many cancers. We hypothesized that the antineoplastic effects of sulindac and its metabolites were due, in part, to targeting downregulation of Sp transcription factors.MethodsThe functional effects of sulindac, sulindac sulfone and sulindac sulfide on colon cancer cell proliferation were determined by cell counting. Effects of these compounds on expression of Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes were determined by western blot analysis of whole cell lysates and in transient transfection assays using GC-rich constructs.ResultsSulindac and its metabolites inhibited RKO and SW480 colon cancer cell growth and the order of growth inhibitory potency was sulindac sulfide > > sulindac sulfone > sulindac. Treatment of SW480 and RKO cells with sulindac sulfide downregulated expression of Sp1, Sp3 and Sp4 proteins. Sulindac sulfide also decreased expression of several Sp-regulated genes that are critical for cancer cell survival, proliferation and angiogenesis and these include survivin, bcl-2, epidermal growth factor receptor (EGFR), cyclin D1, p65 subunit of NFκB and vascular endothelial growth factor (VEGF). Sulindac sulfide also induced reactive oxygen species (ROS) and decreased the level of microRNA-27a in colon cancer cells, which resulted in the upregulation of the Sp-repressor ZBTB10 and this resulted in downregulation of Sp proteins.ConclusionsThe results suggest that the cancer chemotherapeutic effects of sulindac in colon cancer cells are due, in part, to its metabolite sulindac sulfide which downregulates Sp transcription factors and Sp-regulated pro-oncogenic gene products.

Anti-cancer effect of bee venom on colon cancer cell growth by activation of death receptors and inhibition of nuclear factor kappa B.

Bee venom (BV) has been used as a traditional medicine to treat arthritis, rheumatism, back pain, cancerous tumors, and skin diseases. However, the effects of BV on the colon cancer and their action mechanisms have not been reported yet. We used cell viability assay and soft agar colony formation assay for testing cell viability, electro mobility shift assay for detecting DNA binding activity of nuclear factor kappa B (NF-κB) and Western blotting assay for detection of apoptosis regulatory proteins. We found that BV inhibited growth of colon cancer cells through induction of apoptosis. We also found that the expression of death receptor (DR) 4, DR5, p53, p21, Bax, cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 was increased by BV treatment in a dose dependent manner (0-5 μg/ml). Consistent with cancer cell growth inhibition, the DNA binding activity of nuclear factor kappa B (NF-κB) was also inhibited by BV treatment. Besides, we found that BV blocked NF-κB activation by directly binding to NF-κB p50 subunit. Moreover, combination treatment with BV and p50 siRNA or NF-κB inhibitor augmented BV-induced cell growth inhibition. However, p50 mutant plasmid (C62S) transfection partially abolished BV-induced cell growth inhibiton. In addition, BV significantly suppressed tumor growth in vivo. Therefore, these results suggested that BV could inhibit colon cancer cell growth, and these anti-proliferative effects may be related to the induction of apoptosis by activation of DR4 and DR5 and inhibition of NF-κB.

Withaferin-A Inhibits Colon Cancer Cell Growth by Blocking STAT3 Transcriptional Activity.

Background:Withania somnifera (known as Ashwagandha) is a medicinal plant used in the ayurvedic medicines in India. Withaferin-A, a withanolide derived from the leaf extract of W. somnifera, has been reported to exhibit anti-tumor activity against various cancer cells, such as leukemia, breast cancer and colon cancer cells.Methods:We investigated the anti-cancer effects of withaferin-A on the proliferation and migration of human colorectal cancer (HCT116) cells. And we evaluated the effects of withaferin-A on the transcriptional activity of STAT3 and the growth of HCT116 cells in xenograft mouse tumor model.Results:In the present study, we found that withaferin-A inhibited the proliferation and migration of HCT116 cells in a concentration-dependent manner. Treatment of HCT116 cells with withaferin-A attenuated interleukin-6-induced activation of STAT3, which has been implicated in the development and progression of colon cancer. To examine the effect of withaferin-A on HCT116 cells proliferation in vivo, we generated HCT116 cells xenograft tumors in Balb/c nude mice and treated the tumor bearing mice with or without withaferin-A intraperitoneally. Treatment with withaferin-A exhibited significant decrease in the volume and weight of tumors as compared to untreated controls.Conclusions:The present study suggests that withaferin-A holds the potential to be developed as a small molecule inhibitor of STAT3 for the treatment of HCT116.

Methyl Sartortuoate Inhibits Colon Cancer Cell Growth by Inducing Apoptosis and G2/M-Phase Arrest

The potential anti-neoplastic activity of terpenoids is of continued interest. In this study, we investigate whether methyl sartortuoate, a terpenoid isolated from soft coral, induced cell cycle arrest and apoptosis in a human colon cancer cell line. Culture studies found that methyl sartortuoate inhibited colon cancer cell (LoVo and RKO) growth and caused apoptotic death in a concentration- and time-dependent manner, by activation of caspase-8, caspase-9, caspase-3, p53 and Bax, and inactivation of B-cell lymphoma 2 (Bcl-2) apoptosis regulating proteins. Methyl sartortuoate treatment led to reduced expression of cdc2 and up-regulated p21 and p53, suggesting that Methyl sartortuoate induced G2-M arrest through modulation of p53/p21/cdc2 pathways. Methyl sartortuoate also up-regulated phospho-JNK and phospho-p38 expression levels. This resulted in cell cycle arrest at the G2-M phase and apoptosis in LoVo and RKO cells. Treatment with the JNK inhibitor SP600125 and the p38 MAPK inhibitor SB203580 prevented methyl sartortuoate-induced apoptosis in LoVo cells. Moreover, methyl sartortuoate also prevented neoplasm growth in NOD-SCID nude mice inoculated with LoVo cells. Taken together, these findings suggest that methyl sartortuoate is capable of leading to activation of caspase-8, -9, -3, increasing p53 and Bax/Bcl-2 ratio apoptosis through MAPK-dependent apoptosis and results in G2-M phase arrest in LoVo and RKO cells. Thus, methyl sartortuoate may be a promising anticancer candidate.

Synthesis and anti-cancer potential of the positional isomers of NOSH-aspirin (NBS-1120) a dual nitric oxide and hydrogen sulfide releasing hybrid.

We recently reported the synthesis of NOSH-aspirin, a novel hybrid compound capable of releasing both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e., ortho-NOSH-aspirin. Here we report on the synthesis of meta- and para-NOSH-aspirins. We also made a head-to-head evaluation of the effects of these three positional isomers of NOSH-aspirin on colon cancer cell kinetics and induction of reactive oxygen species, which in recent years has emerged as a key event in causing cancer cell regression. Electron donating/withdrawing groups incorporated about the benzoate moiety significantly affected the potency of these compounds with respect to colon cancer cell growth inhibition.