• Biomolecules & Therapeutics
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• 제31권6호
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• pp.655-660
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• 2023

Colorectal cancer (CRC) is one of the most high-risk cancers; however, it has been suggested that estrogen signaling in CRC could have a protective effect. Therefore, we focused on the function of the G protein-coupled estrogen receptor (GPER) among the estrogen receptors in CRC. In this study, we investigated the therapeutic effect of resveratrol via GPER in CRC (RKO and WiDr) cells, CRC cell-derived xenograft models, and organoids (30T and 33T). Resveratrol significantly suppressed cell viability and proliferation in highly GPER-expressing RKO cells compared to that in low GPER-expressing WiDr cells. In xenograft models, resveratrol also delayed tumor growth and exhibited a high survival rate depending on GPER expression in RKO-derived tumors. Furthermore, resveratrol significantly inhibited the viability of organoids with high GPER expression. Additionally, the anticancer effect of resveratrol on CRC showed that resveratrol rapidly responded to GPER, while increasing the expression of p-ERK and Bax and cleaving PARP proteins.

• Asian Pacific Journal of Cancer Prevention
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• 제17권8호
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• pp.4019-4023
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• 2016

Background: Colorectal cancer (CRC) or bowel cancer is one of the most important cancer diseases, needing serious attention. The cell surface receptor gene human epidermal growth factor receptor (EGFR) may have an important role in provoking CRC. In this pharmaceutical era, it is always attempted to identify plant-based drugs for cancer, which will have less side effects for human body, unlike the chemically synthesized marketed drugs having serious side effects. So, in this study the authors tried to assess the activity of two important plant compounds, ferulic acid (FA) and p-coumaric acid (pCA), on CRC. Materials and Methods: FA and pCA were tested for their cytotoxic effects on the human CRC cell line HCT 15 and also checked for the level of gene expression of EGFR by real time PCR analysis. Positive results were confirmed by in silico molecular docking studies using Discovery Studio (DS) 4.0. The drug parallel features of the same compounds were also assessed in silico. Results: Cytotoxicity experiments revealed that both the compounds were efficient in killing CRC cells on a controlled concentration basis. In addition, EGFR expression was down-regulated in the presence of the compounds. Docking studies unveiled that both the compounds were able to inhibit EGFR at its active site. Pharmacokinetic analysis of these compounds opened up their drug like behaviour. Conclusions: The findings of this study emphasize the importance of plant compounds for targeting diseases like CRC.

• 약학회지
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• 제54권3호
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• pp.192-199
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• 2010

Colorectal cancer is one of the most common alimentary malignancies. In this study, the antitumor activity of activated human natural killer (NK) cells against human colorectal cancer was evaluated in vivo. Human NK cells are the key contributors of innate immune response and the effective functions of these cells are enhanced by cytokines. Human peripheral blood mononuclear cells (PBMC) were cultured with interleukin-2 (IL-2)-containing medium for 14 days and resulted in enriched NK cell population. The resulting populations of the cells comprised 7% $CD3^+CD4^+$ cells, 25% $CD3^+CD8^+$ cells, 13% $CD3^-CD8^+$ cells, 4% $CD3^+$CD16/$CD56^+$ cells, 39% $CD3^+$CD16/$CD56^-$ cells, and 52% $CD3^-$CD16/$CD56^+$ cells. Tumor necrosis factor alpha (TNF-$\alpha$), interferon gamma (IFN-$\gamma$), IL-2, IL-4, and IL-5 transcripts of the activated NK cells were confirmed by RT-PCR. In addition, activated NK cells at doses of 2.5, 5 and 10 million cells per mouse inhibited 10%, 34% and 47% of SW620-induced tumor growth in nude mouse xenograft assays, respectively. This study suggests that NK cell-based immunotherapy may be used as an adoptive immunotherapy for colorectal cancer patients.

• Asian Pacific Journal of Cancer Prevention
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• 제15권11호
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• pp.4589-4594
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• 2014

The mammalian target of rapamycin (mTOR) signaling pathway is upregulated in the pathogenesis of many cancers, including colorectal cancer (CRC). DEPTOR is an mTOR inhibitor whose expression is negatively regulated by mTOR. However, the role of DEPTOR in the development of CRC is not known. The aim of this study was to investigate the expression of DEPTOR and mTORC1 activity (P-S6) in a subset of CRC patients and determine their relation to tumor differentiation, invasion, nodal metastasis and disease-free survival. Here, Immunohistochemical expression of P-S6 (S235/236) and DEPTOR were evaluated in 1.5 mm tumor cores from 90 CRC patients and in 90 samples of adjacent normal mucosa by tissue microarray. The expression of P-S6 (S235/236) was upregulated in CRC, with the positive rate of P-S6 (S235/236) in CRC (63.3%) significantly higher than that in control tissues (36.7%, 30%) (p<0.05). P-S6 (S235/236) also correlated with high tumor histologic grade (p=0.002), and positive nodal metastasis (p=0.002). In contrast, the expression level of DEPTOR was correlated with low tumor histological grade (p=0.006), and negative nodal metastasis (p=0.001). Interestingly, P-S6 (S235/236) expression showed a significant negative association with the expression of DEPTOR in CRC (p=0.011, R= -0.279). However, upregulation of P-S6 (S235/236) (p=0.693) and downregulation of DEPTOR (p=0.331) in CRC were not significantly associated with overall survival. Thus, we conclude that expression of DEPTOR negatively correlates with mTORC1 activity and tumor progression in CRC. DEPTOR is a potential marker for prognostic evaluation and a target for the treatment of CRC.

• Journal of Yeungnam Medical Science
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• 제34권2호
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• pp.216-221
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• 2017

Background: This study was conducted to investigate preoperative carcinoembryonic antigen (CEA) as a prognostic factor in colorectal cancer. Methods: Between January 2000 and July 2011, 1298 patients with primary adenocarcinoma colorectal cancer without metastasis, who underwent curative resection were retrospectively identified. The patients were divided into two groups according to serum CEA level at primary diagnosis: a high CEA (HCEA) group (serum CEA ${\geq}6ng/mL$) and a normal CEA (NCEA) group (serum CEA <6 ng/mL). A 1:1 propensity score matching analysis was applied to reduce bias. Finally, 364 patients were enrolled in this study. Matched variables were age, gender, preoperative chemoradiotherapy, tumor site, cell differentiation and pathologic stage. Results: The clinicopathological characteristics of the two groups did not differ significantly difference. The systemic metastasis rate was 16.5% (30/182) and 25.3% (46/182) in the NCEA and HCEA groups, respectively (p=0.039). There were no significant differences in local recurrence or metastatic sites between groups. The 5-year disease-free survival (DFS) rate of the HCEA group was worse than that of the NCEA group; however, there was no significant difference in overall survival between the two groups. Conclusion: Elevated preoperative CEA was related to frequent systemic recurrence and low DFS. Therefore, elevated preoperative CEA could be considered a prognostic factor for worse clinical outcomes in patients with colorectal cancer.

• Biomolecules & Therapeutics
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• 제30권3호
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• pp.257-264
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• 2022

Colorectal cancer (CRC) is one of the most common malignant tumor. 5-FU is commonly used for the treatment of CRC. However, the development of drug resistance in tumor chemotherapy can seriously reduce therapeutic efficacy of 5-FU. Recent data show that FoxM1 is associated with 5-FU resistance in CRC. FoxM1 plays a critical role in the carcinogenesis and drug resistance of several malignancies. It has been reported that urushiol V isolated from the cortex of Rhus verniciflua Stokes is cytotoxic to several types of cancer cells. However, the underlying molecular mechanisms for its antitumor activity and its potential to attenuate the chemotherapeutic resistance in CRC cells remain unknown. Here, we found that urushiol V could inhibit the cell proliferation and induced S-phase arrest of SW480 colon cancer cells. It inhibited protein expression level of FoxM1 through activation of AMPK. We also investigated the combined effect of urushiol V and 5-FU. The combination treatment reduced FoxM1 expression and consequently reduced cell growth and colony formation in 5-FU resistant colon cancer cells (SW480/5-FUR). Taken together, these result suggest that urushiol V from Rhus verniciflua Stokes can suppress cell proliferation by inhibiting FoxM1 and enhance the antitumor capacity of 5-FU. Therefore, urushiol V may be a potential bioactive compound for CRC therapy.

• 동의생리병리학회지
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• 제26권2호
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• pp.155-159
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• 2012

The purpose of this study was to investigate the anti-cancer effects of Sophorae Radix and the effects of 5-Fluorouracil (5-FU) in human colorectal adenocarcinoma cells (HT-29). We used human colorectal adenocarcinoma cell line, HT-29 cells. We examined cell death by MTT assay and caspase 3 assay with Sophorae Radix. To examine the inhibitory effects of Sophorae Radix, cell cycle (sub G1) analysis was done the HT-29 cells after three days with Sophorae Radix. The reversibility of Sophorae Radix was examined on one day to five days treatment with $150{\mu}g$ Sophorae Radix. Sophorae Radix inhibited the growth of HT-29 cells in a dose-dependent fashion. Also we showed that Sophorae Radix induced apoptosis in HT-29 cells by MTT assay, caspase 3 assay and sub-G1 analysis. Sophorae Radix combined with 5-FU markedly inhibited the growth of HT-29 cells compared to Sophorae Radix or 5-FU alone. After 3 days treatment of HT-29 cells with Sophorae Radix, the fraction of cells in sub-G1 phase was much higher than that of the control group. Our findings provide insight into unraveling the effects of Sophorae Radix in human colorectal adenocarcinoma cells and developing therapeutic agents against colorectal cancer.

• Biomolecules & Therapeutics
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• 제30권3호
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• pp.265-273
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• 2022

Resistance to chemotherapeutic drugs is a significant problem in the treatment of colorectal cancer, resulting in low response rates and decreased survival. Recent studies have shown that shikonin, a naphthoquinone derivative, promotes apoptosis in colon cancer cells and cisplatin-resistant ovarian cells, raising the possibility that this compound may be effective in drug-resistant colorectal cancer. The aim of this study was to characterize the molecular mechanisms underpinning shikonin-induced apoptosis, with a focus on endoplasmic reticulum (ER) stress, in a 5-fluorouracil-resistant colorectal cancer cell line, SNU-C5/5-FUR. Our results showed that shikonin significantly increased the proportion of sub-G₁ cells and DNA fragmentation and that shikonin-induced apoptosis is mediated by mitochondrial Ca²⁺ accumulation. Shikonin treatment also increased the expression of ER-related proteins, such as glucose regulatory protein 78 (GRP78), phospho-protein kinase RNA-like ER kinase (PERK), phospho-eukaryotic initiation factor 2 (eIF2α), phospho-phosphoinositol-requiring protein-1 (IRE1), spliced X-box-binding protein-1 (XBP-1), cleaved caspase-12, and C/EBP-homologous protein (CHOP). In addition, siRNA-mediated knockdown of CHOP attenuated shikonin-induced apoptosis, as did the ER stress inhibitor TUDCA. These data suggest that ER stress is a key factor mediating the cytotoxic effect of shikonin in SNU-C5/5-FUR cells. Our findings provide an evidence for a mechanism in which ER stress leads to apoptosis in shikonin-treated SNU-C5/5-FUR cells. Our study provides evidence to support further investigations on shikonin as a therapeutic option for 5-fluorouracil-resistant colorectal cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제17권2호
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• pp.743-748
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• 2016

Background: $K^-Ras$ activation is an early event in colorectal carcinogenesis and associated mutations have been reported in about 40% of colorectal cancer patients. These mutations have always been responsible for enhancing malignancy and silencing them is associated with attenuation of tumorigenicity. Among downstream effectors are the RAF/MEK/ERK and the PI3K/Akt signaling pathways. PI3K/Akt signaling leads to reduction of apoptosis, stimulated cell growth and enhanced proliferation. Ellagic acid (EA), a naturally occurring antioxidant, has recently emerged as a promising anti-cancer agent. Purpose: To evaluate the impact of cellular genetic makeup of two colon cancer cell lines with different genetic backgrounds, HCT-116 ($K^-Ras^-/p53^+$) and Caco-2 ($K^-Ras^+/p53^-$), on response to potential anti-tumour effects of EA. In addition, the influence of $K^-Ras$ silencing in HCT-116 cells was investigated. Materials and Methods: Cellular proliferation, morphology and cell cycle analysis were carried out in addition to Western blotting for detecting total Akt and p-Akt (at Thr308 and Ser473) in the presence and absence of different concentrations of EA. Cell proliferation was also assessed in cells transfected with different concentrations of $K^-Ras$ siRNA or incubated with ellagic acid following transfection. Results: The results of the present study revealed that EA exerts anti-proliferative and dose-dependent pro-apoptotic effects. Cytostatic and cytotoxic effects were also observed. p-Akt (at Thr308 and Ser473) was downregulated. Moreover, EA treatment was found to (i) reduce $K^-Ras$ protein expression; (ii) in cells transfected with siRNA and co-treated with EA, pronounced anti-proliferative effects as well as depletion of p-Akt (at Thr308) were detected. Conclusions: Cellular genetic makeup ($K^-Ras^-/p53^-$) was not likely to impose limitations on targeting EA in treatment of colon cancer. EA had a multi-disciplinary pro-apoptotic anti-proliferative approach, having inhibited Akt phosphorylation, induced cell cycle arrest and showed an anti-proliferative potential in HCT-116 cells (expressing mutant $K^-Ras$).

• Asian Pacific Journal of Cancer Prevention
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• 제17권11호
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• pp.4929-4934
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• 2016

Cancer, a worldwide epidemic disease with diverse origins, involves abnormal cell growth with the potential to invade other parts of the body. Globally, it is the main cause of mortality and morbidity. To overcome the drawbacks of the commercially available chemotherapies, natural products-loaded nano-composites are recommended to improve cancer targetability and decrease the harmful impact on normal cells. This study aimed at exploring the anti-cancer impacts of Moringa oleifera seed oil in its free- (MO) and nano-formulations (MOn) through studying whether it mechanistically promotes mitochondrial apoptosis-mediating cell death. Mitochondrial-based cytotoxicity and flow cytometric-based apoptosis analyses were performed on cancer HepG2, MCF7, HCT 116, and Caco-2 cell lines against normal kidney BHK-21 cell line. The present study resulted that MOn triggered colorectal cancer Caco-2 and HCT 116 cytotoxicity via mitochondrial dysfunction more powerful than its free counterpart (MO). On the other side, MOn and MO remarkably induces HCT 116 mitochondrial apoptosis, while sparing normal BHK-21 cells with minimal cytotoxic effect. The present results concluded that nano-micelle of Moringa oleifera seed oil (MOn) can provide a novel therapeutic approach for colorectal and breast cancers via mitochondrial-mediated apoptosis, while sparing normal and even liver cancer cells a bit healthy or with minimal harmful effect. Intriguingly, MOn induced breast cancer not hepatocellular carcinoma cell death.