Necrosis predominates in the cell death of human colon adenocarcinoma HT-29 cells treated under variable conditions of photodynamic therapy with hypericin.

Photodynamic therapy (PDT) represents a new rapidly-developing anticancer approach based on administration of a non- or weakly-toxic photosensitizer and its activation with light of appropriate wavelength. Hypericin, one of the promising photosensitizers, is known to induce apoptosis with high efficiency in various cell line models. However, here we report the prevalence of necrosis accompanied by suppression of caspase-3 activation in colon adenocarcinoma HT-29 cells exposed to an extensive range of PDT doses evoked by variations in two variables -- hypericin concentration and light dose. Necrosis was the principal mode of cell death despite different PDT doses and the absence of anti-apoptotic Bcl-2 expression, even if the same condition induced caspase-3 activity at similar toxicity in HeLa cells. Introduction of Bcl-2 into HT-29 cells invoked caspase-3 activation, changed the Bcl-X(L) expression pattern, increased the apoptosis ratio with no effect on overall toxicity, and supported arrest in the G(2)/M-phase of cell cycle. Since it is known that Bcl-2 suppression in HT-29 is reversible and linked to the over-expression of mutated p53 and also considering our data, we suggest that the mutation in p53 and events linked to this feature may play a role in cell death signalling in HT-29 colon cancer cells.     

The NF-kappa B cascade is important in Bcl-xL expression and for the anti-apoptotic effects of the CD28 receptor in primary human CD4+ lymphocytes

We explored the role of the NF-kappa B pathway in the survival of primary human CD4+ T lymphocytes during CD28 costimulation. Transduction of proliferating CD4+ T cells with a tetracycline-regulated retrovirus encoding for a dominant-interfering, degradation-resistant I-kappaBalpha (inhibitor of kappa B alpha factor) mutant induced apoptosis. Using DNA arrays, we show that Bcl-xL features as a prominent anti-apoptotic member among a number of early CD28-inducible genes. A 1.2-kb segment of the proximal Bcl-xL promoter, linked to a luciferase reporter, responded to CD3/CD28 stimulation in Jurkat cells. Mutation of an NF-kappa B site around -840 decreased, while ectopic expression of I-kappa B kinase-beta (IKK beta) enhanced reporter gene activity. Na+-salicylate and cyclopentenone PGs, direct inhibitors of IKK beta, interfered in the activation of the Bcl-xL promoter and induced apoptosis in CD28-costimulated CD4+ T cells. Moreover, salicylate blocked nuclear localization of NF-kappa B factors that bind to the NF-kappa B binding site in the Bcl-xL promoter, as well as the expression of Bcl-xL protein. HuT-78, a lymphoblastoid T cell line with constitutive NF-kappa B activity, contained elevated levels of Bcl-xL protein and, similar to proliferating CD4+ T cells, was resistant to apoptotic stimuli such as anti-Fas and TNF-alpha. In contrast, the same stimuli readily induced apoptosis in a Jurkat T cell clone with no detectable Bcl-xL expression. Jurkat BMS2 cells also differed from HuT-78 in collapse of mitochondrial membrane potential and superoxide generation in the mitochondrium. Taken together, these data demonstrate that CD3/CD28-induced activation of IKK beta and expression of Bcl-xL promote the survival of primary human CD4+ T lymphocytes.     

NF-kappaB pathway is involved in griseofulvin-induced G2/M arrest and apoptosis in HL-60 cells

Griseofulvin (GF), an oral antifungal agent, has been shown to exert antitumorigenesis effect through G2/M cell cycle arrest in colon cancer cells. But the underlying mechanisms remained obscure. The purpose of this study is to test the cytotoxic effect of GF on HL-60 and HT-29 cells and elucidate its underlying molecular pathways. Dose-dependent and time-course studies by flow cytometry demonstrated that 30 to 60 microM GF significantly induced G2/M arrest and to a less extend, apoptosis, in HL-60 cells. In contrast, only G2/M arrest was observed in HT-29 cells under similar condition. Pretreatment of 30 microM TPCK, a serine protease inhibitor, completely reversed GF-induced G2/M cell cycle arrest and apoptosis in HL-60 cells but not in HT-29 cells. The GF-induced G2/M arrest in HL-60 cells is reversible. Using EMSA and super-shift analysis, we demonstrated that GF stimulated NF-kappaB binding activity in HL-60 cells, which was completely inhibited by pretreatment of TPCK. Treatment of HL-60 with 30 microM GF activated JNK but not ERK or p38 MAPK and subsequently resulted in phosphorylation of Bcl-2. Pretreatment of TPCK to HL-60 cells blocked the GF-induced Bcl-2 phosphorylation but not JNK activation. Time course study demonstrated that activation of cdc-2 kinase activity by GF correlated with Bcl-2 phosphorylation. Taken together, our results suggest that activation of NF-kappaB pathway with cdc-2 activation and phosphorylation of Bcl-2 might be involved in G2/M cell cycle arrest in HL-60 cells.     

Brefeldin A Is a Potent Inducer of Apoptosis in Human Cancer Cells Independently of p53

Brefeldin A (BFA) is a natural product that affects the structure and function of the Golgi apparatus and is in development for cancer chemotherapy. We observed that a wide range of cancer cells could undergo DNA fragmentation associated with apoptosis after BFA treatment. This DNA fragmentation was induced within 15 h in HL60 leukemia cells and after 48 h in K562 leukemia and HT-29 colon carcinoma cells with BFA concentrations as low as 0.1 μM.The DNA fragmentation had the typical internucleosomal pattern in HL60 and HT-29 cells. Apoptotic cells were also detected by microscopy. BFA-induced apoptosis is p53-independent as HL60 and K562 cells are p53 null and HT-29 are p53 mutant cells. BFA could potentiate UCN-01 and staurosporine-induced DNA fragmentation in HL60 cells. Cyclin B1/Cdc2 kinase activity decreased after BFA treatment in HL60 cells, indicating that BFA-induced DNA fragmentation was independent of a cyclin B1/Cdc2 kinase upregulation pathway. Cycloheximide could not prevent BFA-induced DNA fragmentation in HL60 cells, suggesting that protein synthesis is not needed for HL60 cells to undergo apoptosis. On the contrary, cycloheximide blocked BFA-induced DNA fragmentation in HT-29 cells, indicating that apoptosis in HT-29 cells requires macromolecular synthesis. Cell-free system experiments suggested that cytosolic proteins play an important role in triggering DNA fragmentation during apoptosis induced by BFA. Our results show that transduction signaling pathways play central roles in apoptotic regulation.     

Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and NF-kappaB in human colon cancer

Peroxisome-proliferator activated receptor-gamma (PPARgamma) has been demonstrated to exert an inhibitory effect on cell growth in most cell types studied, but its role in colon cancer is still uncertain. The molecular mechanism between the activation of PPARgamma and its consequence is unknown. In the present report, we show that the expression of PPARgamma was significantly increased in tumor tissues from human colon cancer compared with non-tumor tissues and that PPARgamma ligands, 15-Deoxy-delta(12,14)prostaglandin J2 or ciglitizone, induced apoptosis in HT-29 cells, a human colon cancer cell line. The occurrence of apoptosis induced by PPARgamma ligands was sequentially accompanied by reduced levels of NF-kappaB and Bcl-2. Over-expression of Bcl-2 significantly protected the cells from apoptosis. This study suggested that a PPARgamma-Bcl-2 feedback loop may function to control the life-death continuum in colonic cells and that a deficiency in generation of PPARgamma ligands may precede the development of human colon cancer.     

Cell cycle arrest and apoptosis induced by methyl 3,5-dicaffeoyl quinate in human colon cancer cells: Involvement of the PI3K/Akt and MAP kinase pathways

Methyl 3,5-dicaffeoyl quinate (MDQ) is a flavonoid glucoside found in several plants that scavenges 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals and peroxynitrite, and inhibits the formation of cholesteryl ester hydroperoxide during the copper ion-induced oxidation of blood plasma in rats. In this study, MDQ inhibited proliferation and induced apoptosis in HT-29 cells in a dose-dependent manner as detected by 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), trypan blue exclusion, and flow cytometric assays. Western blot analysis showed that apoptosis was dependent on caspase-3 activity. PARP cleavage and the cytosolic release of cytochrome c from mitochondria increased significantly. In addition, these events were accompanied by a collapse in the mitochondrial membrane potential and a decreased Bcl-2/Bax ratio. Furthermore, the MDQ-induced G₀/G₁ arrest was correlated with an increase in p27 and a decrease in cyclin D1 and p53. MDQ also inhibited the phosphorylation of PI3K/Akt and ERK; significantly reduced NF-κB; and in general displayed a significant anti-proliferative effect via a cell cycle arrest and apoptotic induction in HT-29 cells. These results suggest that MDQ has therapeutic potential against human colon carcinoma.     

Targeting nuclear factor-kappa B activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis

Thymoquinone (TQ), derived from the medicinal plant Nigella sativa, exhibits antiinflammatory and anticancer activities through mechanism(s) that is not fully understood. Because numerous effects modulated by TQ can be linked to interference with the nuclear factor-kappaB (NF-kappa B) signaling, we investigated in detail the effect of this quinone on NF-kappa B pathway. As examined by DNA binding, we found that TQ suppressed tumor necrosis factor-induced NF-kappa B activation in a dose- and time-dependent manner and inhibited NF-kappaB activation induced by various carcinogens and inflammatory stimuli. The suppression of NF-kappaB activation correlated with sequential inhibition of the activation of I kappa B alpha kinase, I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-kappa B-dependent reporter gene expression. TQ specifically suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by DTT. However, TQ did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine residue 38 mutated to serine. TQ also down-regulated the expression of NF-kappa B-regulated antiapoptotic (IAP1, IAP2, XIAP Bcl-2, Bcl-xL, and survivin), proliferative (cyclin D1, cyclooxygenase-2, and c-Myc), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by tumor necrosis factor and chemotherapeutic agents. Overall, our results indicate that the anticancer and antiinflammatory activities previously assigned to TQ may be mediated in part through the suppression of the NF-kappa B activation pathway, as shown here, and thus may have potential in treatment of myeloid leukemia and other cancers.     

Quercetin decreases the expression of ErbB2 and ErbB3 proteins in HT-29 human colon cancer cells

Quercetin has chemoprotective properties in experimental colon cancer models, and in vitro studies have demonstrated that quercetin inhibits HT-29 colon cancer cell growth. ErbB2 and ErbB3 receptor tyrosine kinases have been associated with the development of human colon cancer, and the expressions of both receptors are high in HT-29 cells. In this study, we assessed quercetin regulation of HT-29 and SW480 cell apoptosis and the influence of quercetin on the protein expression of ErbB2, ErbB3, Akt, Bax and Bcl-2. We cultured HT-29 cells in the presence of various concentrations (0, 25, 50, or 100 micromol/L) of quercetin or rutin. Quercetin inhibited HT-29 cell growth in a dose-dependent manner, whereas rutin had no effect on the cell growth. DNA that was isolated from cells treated with 50 micromol/L of quercetin exhibited an oliogonucleosomal laddering pattern characteristic of apoptotic cell death. Western blot analysis of cell lysates revealed that Bcl-2 levels decreased dose-dependently in cells treated with quercetin, but Bax remained unchanged. Quercetin increased levels of cleaved caspase-3 and the 89-kDa fragment of poly (ADP-ribose) polymerase. In addition, phosphorylated Akt levels were markedly lower in cells treated with 25 micromol/L quercetin, but total Akt levels decreased only at 100 micromol/L quercetin. Furthermore, a dose-dependent decrease in ErbB2 and ErbB3 levels was detected in quercetin-treated cells. The results obtained using SW480 cells were similar to those obtained with HT-29 cells. In conclusion, we have shown that quercetin inhibits cell growth and induces apoptosis in colon cancer cells, and that this may be mediated by its ability to down-regulate ErbB2/ErbB3 signaling and the Akt pathway.     

Anti-cancer effects of pyrazole-platinum(II) complexes combined with anti-MUC1 monoclonal antibody versus monotherapy in DLD-1 and HT-29 colon cancer cells

The membrane-bound MUC1 mucin is overexpressed and aberrantly glycosylated in many epithelium origin cancers. One of the promising strategies in cancer therapy is combining monoclonal antibodies against cancer related antigens, like MUC1, with chemotherapeutics. In the study we evaluated the potency of cisplatin (cisPt), two pyrazole-platinum(II) complexes PtPz4, PtPz6, and anti-MUC1 mAb applied as monotherapy, as well as the chemotherapeutics administrated with antibody, towards apoptotic response and cancer-related carbohydrate antigens (TACAs) in DLD-1 and HT-29 colon cancer cells. To assess the impact of the tested compounds on the examined factors flow cytometry, RT-PCR, Western blotting and ELISA were utilized. The combined therapy was more potent than monotherapy towards Bcl-2, Bid, caspases and TACAs of both cell lines. Combined therapy applied in DLD-1 cells induced apoptosis, was more effective than monotherapy in relation to p53, Bcl-xL, Bax, and Bim. In HT-29 cells, anti-MUC1 administrated with the drugs was more potent than monotherapy towards Bad. The proposed anti-MUC1/cisPt and pyrazole-platinum(II) complexes PtPz4, PtPz6 combined therapy may be promising anti-colon cancer therapy.     

Cyclotrisiloxan and β-Sitosterol rich Cassia alata (L.) flower inhibit HT-115 human colon cancer cell growth via mitochondrial dependent apoptotic stimulation

Cancer traits dependent chemo and radiotherapy display acute toxicity and long-term side effects. Since last two decades, researchers investigated a new anticancer agents derived from plants. Cassia alata (L.) is a medicinal herb distributed in the tropical and humid regions. In this study, C. alata flower methanol extract (CME) have been prepared using cold percolation method and the phytochemical components were identified using GC–MS analysis. CME have been used to study the antiproliferative and apoptosis properties against human colon cancer HT-115 colon cancer cells, its molecular mechanism have been explored. 0.2 mg/mL dose of CME, inhibited 50% of HT-115 colon cancer cell growth after 48hr was confirmed the significant antiproliferation effect. In normal cells such as Vero cells and hMSCs, 0.2 mg/mL dose of CME shown only 4% and 5% growth inhibition confirmed the HT-115 cell specific cytotoxic effect. This effect might be due to the availability of phytoactive biomolecules in CME such as, cyclotrisiloxan, beta-sitosterol and alpha-tocopherol have been confirmed by GC–MS. Most interestingly, PI and AO/ErBr staining of CME treated HT-115 cells shown early (25%), pro (17%) and late (8%) apoptotic and 3% necrotic cells after 48 hr. Treatment with CME extract showed potential effect on the inhibition of protumorigenic inflammatory and oxidative stress genes. Protumorigenic COX-2/PGE-2 and TNF-α/NF-κB immune axis were normalized after CME treatment. Amounts of both apoptosis related mRNA p53, Bax, caspase 3 and p21 genes were upregulated, whereas it resulted in significant reduction in the anti-apoptotic marker mdm2 and Bcl-2 genes. In conclusion, bioactive compounds present in CME potentially inhibit HT-115 colon cancer cell proliferation via an inhibition of protumorigenic immune axis and stimulation of mitochondria dependent apoptotic pathway without necrotic effect.     

Prosurvival Bcl-2 proteins stabilize pancreatic mitochondria and protect against necrosis in experimental pancreatitis

Acinar cells in pancreatitis die through apoptosis and necrosis, the roles of which are different. The severity of experimental pancreatitis correlates directly with the extent of necrosis and inversely, with apoptosis. Apoptosis is mediated by the release of cytochrome c into the cytosol followed by caspase activation, whereas necrosis is associated with the mitochondrial membrane potential (ΔΨm) loss leading to ATP depletion. Here, we investigate the role of Bcl-2 proteins in apoptosis and necrosis in pancreatitis. We found up-regulation of prosurvival Bcl-2 proteins in pancreas in various experimental models of acute pancreatitis, most pronounced for Bcl-xL. This up-regulation translated into increased levels of Bcl-xL and Bcl-2 in pancreatic mitochondria. Bcl-xL/Bcl-2 inhibitors induced ΔΨm loss and cytochrome c release in isolated mitochondria. Corroborating the results on mitochondria, Bcl-xL/Bcl-2 inhibitors induced ΔΨm loss, ATP depletion and necrosis in pancreatic acinar cells, both untreated and hyperstimulated with CCK-8 (in vitro pancreatitis model). Together Bcl-xL/Bcl-2 inhibitors and CCK induced more necrosis than either treatment alone. Bcl-xL/Bcl-2 inhibitors also stimulated cytochrome c release in acinar cells leading to caspase-3 activation and apoptosis. However, different from their effect on pronecrotic signals, the stimulation by Bcl-xL/Bcl-2 inhibitors of apoptotic responses was less in CCK-treated than control cells. Therefore, Bcl-xL/Bcl-2 inhibitors potentiated CCK-induced necrosis but not apoptosis. Correspondingly, transfection with Bcl-xL siRNA stimulated necrosis but not apoptosis in the in vitro pancreatitis model. Further, in animal models of pancreatitis Bcl-xL up-regulation inversely correlated with necrosis, but not apoptosis. Results indicate that Bcl-xL and Bcl-2 protect acinar cells from necrosis in pancreatitis by stabilizing mitochondria against death signals. We conclude that Bcl-xL/Bcl-2 inhibition would aggravate acute pancreatitis, whereas Bcl-xL/Bcl-2 up-regulation presents a strategy to prevent or attenuate necrosis in pancreatitis.     

Inhibition of proinflammatory cytokine-induced invasiveness of HT-29 cells by chitosan oligosaccharide

The effect of chitosan oligosaccharide (COS, 1 kDa 相似文献   

Glycine-extended gastrin stimulates proliferation and inhibits apoptosis in colon cancer cells via cyclo-oxygenase-independent pathways

Glycine-extended gastrin (G-Gly) is an end product of processing of the progastrin precursor peptide that has a different spectrum of activity to amidated gastrin. G-Gly promotes cell proliferation in normal and malignant colonic epithelium but the mechanisms responsible are poorly understood. Prostaglandins produced by the cyclo-oxygenase (COX) enzymes have been implicated as downstream mediators of several growth factors, and COX inhibitors such as non-steroidal anti-inflammatory drugs inhibit the proliferation and invasiveness of colonic cancer and reduce the incidence of colon cancer. We have examined the mechanisms of the actions of G-Gly in HT-29 colon cancer cells. G-Gly induced a dose-dependent increase in cell proliferation that was insensitive to inhibition of either COX-1 or COX-2, but was abolished by inhibition of the p38 MAP kinase, ERK and NF-kappaB pathways. G-Gly did not increase prostaglandin E2 production. Celecoxib induced apoptosis and reduced viable cell numbers in a COX-independent manner. G-Gly significantly reduced serum-starvation and celecoxib-induced apoptosis and this effect was also blocked by inhibition of the p38 MAP kinase, ERK and NF-kappaB pathways. Stimulation of HT-29 cells with G-Gly led to a rapid increase in ERK and p38 MAP kinase phosphorylation and increased nuclear translocation of active NF-kappaB. Activation of NF-kappaB was independent of ERK and p38 MAP kinase. G-Gly stimulates proliferation and inhibits apoptosis in colon cancer cells via COX-independent and ERK-, p38 MAP kinase-, and NF-kappaB-dependant pathways. Locally and systemically produced G-Gly may be important in reducing the beneficial effects of chemopreventative agents in colon cancer.     

ZBP-89-induced apoptosis is p53-independent and requires JNK

ZBP-89 induces apoptosis in human gastrointestinal cancer cells through a p53-independent mechanism. To understand the apoptotic pathway regulated by ZBP-89, we identified downstream signal transduction targets. Ectopic expression of ZBP-89 induced apoptosis through the mitochondrial pathway and was accompanied by activation of all three MAP kinase subfamilies: JNK1/2, ERK1/2 and p38 MAP kinase. ZBP-89-induced apoptosis was markedly enhanced by ERK inhibition with U0126. In contrast, inhibiting JNK with a JNK1-specific peptide inhibitor or dominant-negative JNK2 expression abrogated ZBP-89-mediated apoptosis. The p38 inhibitor SB202190 had no effect on ZBP-89-induced cell death. Protein dephosphorylation assays revealed that ZBP-89 activates JNK via repression of JNK dephosphorylation. Oligonucleotide microarray analyses revealed that ectopic expression of ZBP-89 downregulated expression of the dual-specificity phosphatase MKP6. Overexpression of MKP6 blocked ZBP-89-induced JNK phosphorylation and PARP cleavage. In addition, ectopic expression of ZBP-89 repressed Bcl-xL and Mcl-1 expression, but had no effect on Bcl-2. Silencing ZBP-89 with small interfering RNA enhanced both Bcl-xL and Mcl-1 expression. Taken together, ZBP-89-mediated apoptosis occurs via a p53-independent mechanism that requires JNK activation.     

Vinblastine-induced apoptosis is mediated by discrete alterations in subcellular location, oligomeric structure, and activation status of specific Bcl-2 family members

To gain a broader insight into the role of Bcl-2 proteins in apoptosis induced after mitotic arrest, we investigated the subcellular location, oligomeric structure, and protein interactions of Bax, Bcl-2, and Bcl-xL in vinblastine-treated KB-3 cells. Vinblastine induced the translocation of Bax from the cytosol to the mitochondria, which was accompanied by conformational activation and oligomerization of Bax. Bcl-2 was located in the mitochondria, underwent multisite phosphorylation after vinblastine treatment, and was strictly monomeric under all conditions. In contrast, in control cells, Bcl-xL existed in both monomeric (30 kDa) and oligomeric (150 kDa) forms. Treatment with agents that induced Bcl-xL phosphorylation (microtubule inhibitors) caused loss of the 150-kDa form, but this species was unaffected by apoptotic stimuli that did not stimulate phosphorylation. Vinblastine also promoted Bax activation and Bax oligomerization in HCT116 colon cancer cells. Both wild-type and Bax-deficient HCT116 cells expressed the 150-kDa form of Bcl-xL, which was depleted similarly in both cell lines upon vinblastine treatment. Co-immunoprecipitation studies revealed that in untreated KB-3 cells inactive cytosolic Bax interacted with Bcl-xL, whereas in vinblastine-treated cells, activated mitochondrial Bax did not interact with Bcl-xL. Interaction of Bcl-2 with Bax was not observed under any condition. Overexpression of Bcl-xL inhibited vinblastine-induced Bax activation and Bax dimerization and in parallel inhibited apoptosis. The results indicate that vinblastine-induced apoptosis requires translocation, activation, and oligomerization of Bax and is associated with specific changes in the oligomeric properties of Bcl-xL, which occur independently of Bax.     

Cyclotrisiloxan and β-Sitosterol rich Cassia alata (L.) flower inhibit HT-115 human colon cancer cell growth via mitochondrial dependent apoptotic stimulation

Cancer traits dependent chemo and radiotherapy display acute toxicity and long-term side effects. Since last two decades, researchers investigated a new anticancer agents derived from plants. Cassia alata (L.) is a medicinal herb distributed in the tropical and humid regions. In this study, C. alata flower methanol extract (CME) have been prepared using cold percolation method and the phytochemical components were identified using GC–MS analysis. CME have been used to study the antiproliferative and apoptosis properties against human colon cancer HT-115 colon cancer cells, its molecular mechanism have been explored. 0.2 mg/mL dose of CME, inhibited 50% of HT-115 colon cancer cell growth after 48hr was confirmed the significant antiproliferation effect. In normal cells such as Vero cells and hMSCs, 0.2 mg/mL dose of CME shown only 4% and 5% growth inhibition confirmed the HT-115 cell specific cytotoxic effect. This effect might be due to the availability of phytoactive biomolecules in CME such as, cyclotrisiloxan, beta-sitosterol and alpha-tocopherol have been confirmed by GC–MS. Most interestingly, PI and AO/ErBr staining of CME treated HT-115 cells shown early (25%), pro (17%) and late (8%) apoptotic and 3% necrotic cells after 48 hr. Treatment with CME extract showed potential effect on the inhibition of protumorigenic inflammatory and oxidative stress genes. Protumorigenic COX-2/PGE-2 and TNF-α/NF-κB immune axis were normalized after CME treatment. Amounts of both apoptosis related mRNA p53, Bax, caspase 3 and p21 genes were upregulated, whereas it resulted in significant reduction in the anti-apoptotic marker mdm2 and Bcl-2 genes. In conclusion, bioactive compounds present in CME potentially inhibit HT-115 colon cancer cell proliferation via an inhibition of protumorigenic immune axis and stimulation of mitochondria dependent apoptotic pathway without necrotic effect.