Short Hairpin RNA-Mediated Inhibition of Bcl-2 Gene Increases Susceptibility to Methotrexate and Suppresses Lymphoma Growth In Vitro and In Vivo.

Abstract A high level of expression of Bcl-2 is associated with resistance to chemotherapeutic agents and radiation in a number of tumor types, so that a drug to reduce the levels of this protein would be expected to promote apoptosis and would therefore be considered a promising chemotherapeutic agent. At present, gene repression can also be achieved in mammalian cells by using vectors to express small hairpin RNA (shRNA) with a U6 or H1 promoter under the direction of RNA polymerase III. In our lab, we have constructed a U6 promoter based vector expressing shRNA structure targeting against Bcl-2, which could effectively down-regulate Bcl-2 protein. We previously demonstrated that this Bcl-2 shRNA decreased cell proliferation and enhanced radiation-induced apoptosis in Raji cells. In this study, we investigated the synergistic effect of Bcl-2 shRNA combined with methotrexate (MTX) in Molt4, Raji cells and nude mice model bearing human lymphoma.Bcl-2 shRNA was transfected into Molt4 cells and Raji cells with Lipofectamine. At 24,48,72,96 hours after transient transfection, the expression levels of Bcl-2 mRNA and protein were detected by RT-PCR and Western blot. The inhibition of cell growth was assessed by MTT assay, counting cell number. Apoptosis was determined by morphological observation and flow cytomertry. To examine the effect of Bcl-2 shRNA on proliferation and chemosensitivity against MTX in vivo, human Raji cell line was inoculated into the skin of BALB/c nude mice to establish lymphoma model. After Molt4 and Raji cells were transfected with Bcl-2 shRNA, protein and mRNA levels of Bcl-2 obviously were decreased. MTT assays indicated that the growth of cells transfected with Bcl-2 shRNA were significantly lower than those cells with negative control shRNA and untransfected cells, respectively (P<0.05). Bcl-2 shRNA combined with MTX significantly inhibited the growth of cells (P<0.05). There was no difference in cell survival between control shRNA / MTX combination and cells treated with MTX alone. Using Giemsa staining, cells treated with Bcl-2 shRNA combined with MTX displayed changes of apoptosis. Apoptotic rates of both Molt4 and Raji cells treated with Bcl-2 shRNA combined with MTX significantly increased (P<0.05), compared with either control shRNA / MTX combination or MTX-treatment cells alone. In the assay of s.c. tumors in nude mice, tumor growth was inhibited in Bcl-2 shRNA group compared with that in negative control shRNA, and immunohistochemistry showed that Bcl-2 protein level of tumor was also decreased. The inhibition rate of tumor growth was significantly higher in tumors treated with Bcl-2 shRNA combined with MTX than in either control shRNA / MTX combination or MTX-treatment group (P<0.05). These results suggest that Bcl-2 shRNA increases MTX-induced apoptosis in Molt4 and Raji cells. Moreover, the combination of Bcl-2 shRNA and MTX produces greater antitumor effect.

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Circular RNA circCSPP1 knockdown attenuates doxorubicin resistance and suppresses tumor progression of colorectal cancer via miR-944/FZD7 axis

Cancer Cell International ◽

10.1186/s12935-021-01855-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Lanlan Xi ◽

Quanlin Liu ◽

Wei Zhang ◽

Linshan Luo ◽

Jingfeng Song ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Growth ◽

Circular Rna ◽

Luciferase Reporter ◽

Circular Rnas ◽

Protein Levels ◽

Cell Progression ◽

Rna Immunoprecipitation ◽

Induced Apoptosis

Abstract Background Circular RNAs (circRNAs) have been reported to play vital roles in colorectal cancer (CRC). However, only a few circRNAs have been experimentally validated and functionally described. In this research, we aimed to reveal the functional mechanism of circCSPP1 in CRC. Methods 36 DOX sensitive and 36 resistant CRC cases participated in this study. The expression of circCSPP1, miR-944 and FZD7 were detected by quantitative real time polymerase chain reaction (qRT-PCR) and the protein levels of FZD7, MRP1, P-gp and LRP were detected by western blot. Cell proliferation, migration, invasion, and apoptosis were assessed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay, transwell assay, or flow cytometry analysis, respectively. The interaction between miR-944 and circCSPP1 or frizzled-7 (FZD7) was predicted by Starbase 3.0 and verified by the dual luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull down assay. Xenograft tumor assay was performed to examine the effect of circCSPP1 on tumor growth in vivo. Results The expression of circCSPP1 and FZD7 was upregulated while miR-944 expression was downregulated in doxorubicin (DOX)-resistant CRC tissues and cells. CircCSPP1 knockdown significantly downregulated enhanced doxorubicin sensitivity, suppressed proliferation, migration, invasion, and induced apoptosis in DOX-resistant CRC cells. Interestingly, we found that circCSPP1 directly downregulated miR-944 expression and miR-944 decreased FZD7 level through targeting to 3′ untranslated region (UTR) of FZD7. Furthermore, circCSPP1 mediated DOX-resistant CRC cell progression and doxorubicin sensitivity by regulating miR-944/FZD7 axis. Besides, circCSPP1 downregulation dramatically repressed CRC tumor growth in vivo. Conclusion Our data indicated that circCSPP1 knockdown inhibited DOX-resistant CRC cell growth and enhanced doxorubicin sensitivity by miR-944/FZD7 axis, providing a potential target for CRC therapy.

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Anti-Cancer Effects of Zotarolimus Combined with 5-Fluorouracil Treatment in HCT-116 Colorectal Cancer-Bearing BALB/c Nude Mice

Molecules ◽

10.3390/molecules26154683 ◽

2021 ◽

Vol 26 (15) ◽

pp. 4683

Author(s):

Geng-Ruei Chang ◽

Chan-Yen Kuo ◽

Ming-Yang Tsai ◽

Wei-Li Lin ◽

Tzu-Chun Lin ◽

...

Keyword(s):

Growth Factor ◽

Tumor Growth ◽

Nude Mice ◽

Colorectal Adenocarcinoma ◽

Transforming Growth Factor ◽

Colon Adenocarcinoma ◽

Future Research ◽

Related Factors ◽

Hct 116

Zotarolimus is a semi-synthetic derivative of rapamycin and an inhibitor of mammalian target of rapamycin (mTOR) signaling. Currently, zotarolimus is used to prolong the survival time of organ grafts, but it is also a novel immunosuppressive agent with potent anti-proliferative activity. Here, we examine the anti-tumor effect of zotarolimus, alone and in combination with 5-fluorouracil, on HCT-116 colorectal adenocarcinoma cells implanted in BALB/c nude mice. Compared with the control mice, mice treated with zotarolimus or zotarolimus combined with 5-FU showed retarded tumor growth; increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase (ERK) phosphorylation; reduced inflammation-related factors such as IL-1β, TNF-α, and cyclooxygenase-2 (COX-2) protein; and inhibited metastasis-related factors such as CD44, epidermal growth factor receptor (EGFR), transforming growth factor β (TGF-β), and vascular endothelial growth factor (VEGF). Notably, mice treated with a combination of zotarolimus and 5-FU showed significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with mice treated with 5-FU or zotarolimus alone, indicating a strong synergistic effect. This in vivo study confirms that zotarolimus or zotarolimus combined with 5-FU can be used to retard colorectal adenocarcinoma growth and inhibit tumorigenesis. Our results suggest that zotarolimus may increase the chemo-sensitization of tumor cells. Therefore, zotarolimus alone and zotarolimus combined with 5-FU may be potential anti-tumor agents in the treatment of human colon adenocarcinoma. Future research on zotarolimus may lead to the development of new therapeutic strategies.

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The Anti-Cancer Effects of a Zotarolimus and 5-Fluorouracil Combination Treatment on A549 Cell-Derived Tumors in BALB/c Nude Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22094562 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4562

Author(s):

Ching-Feng Wu ◽

Ching-Yang Wu ◽

Robin Y.-Y. Chiou ◽

Wei-Cheng Yang ◽

Chuen-Fu Lin ◽

...

Keyword(s):

Growth Factor ◽

Tumor Growth ◽

Lung Adenocarcinoma ◽

Nude Mice ◽

Transforming Growth Factor ◽

Human Lung ◽

Transforming Growth Factor Β ◽

Related Factors ◽

Human Lung Adenocarcinoma

Zotarolimus is a semi-synthetic derivative of rapamycin and a novel immunosuppressive agent used to prevent graft rejection. The pharmacological pathway of zotarolimus restricts the kinase activity of the mammalian target of rapamycin (mTOR), which potentially leads to reductions in cell division, cell growth, cell proliferation, and inflammation. These pathways have a critical influence on tumorigenesis. This study aims to examine the anti-tumor effect of zotarolimus or zotarolimus combined with 5-fluorouracil (5-FU) on A549 human lung adenocarcinoma cell line implanted in BALB/c nude mice by estimating tumor growth, apoptosis expression, inflammation, and metastasis. We established A549 xenografts in nude mice, following which we randomly divided the mice into four groups: control, 5-FU (100 mg/kg/week), zotarolimus (2 mg/kg/day), and zotarolimus combined with 5-FU. Compared the results with those for control mice, we found that mice treated with zotarolimus or zotarolimus combined with 5-FU retarded tumor growth; increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase (ERK) phosphorylation; decreased inflammation cytokines levels (e.g., IL-1β, TNF-α, and IL-6); reduced inflammation-related factors such as cyclooxygenase-2 (COX-2) protein and nuclear factor-κB (NF-κB) mRNA; enhanced anti-inflammation-related factors including IL-10 and inhibitor of NF-κB kinase α (IκBα) mRNA; and inhibited metastasis-related factors such as transforming growth factor β (TGF-β), CD44, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF). Notably, mice treated with zotarolimus combined with 5-FU had significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with the groups of mice treated with 5-FU or zotarolimus alone. The in vivo study confirmed that zotarolimus or zotarolimus combined with 5-FU could retard lung adenocarcinoma growth and inhibit tumorigenesis. Zotarolimus and 5-FU were found to have an obvious synergistic tumor-inhibiting effect on lung adenocarcinoma. Therefore, both zotarolimus alone and zotarolimus combined with 5-FU may be potential anti-tumor agents for treatment of human lung adenocarcinoma.

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Alantolactone inhibits cell autophagy and promotes apoptosis via AP2M1 in acute lymphoblastic leukemia

Cancer Cell International ◽

10.1186/s12935-020-01537-9 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Ce Shi ◽

Wenjia Lan ◽

Zhenkun Wang ◽

Dongguang Yang ◽

Jia Wei ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Tumor Growth ◽

Cell Lines ◽

Lymphoblastic Leukemia ◽

Dependent Manner ◽

Nude Mouse Model ◽

Hematopoietic Malignancy ◽

Induced Apoptosis ◽

Anti Tumor Activity

Abstract Background Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most commonly observed in children. Alantolactone (ALT) has been reported to exhibit anti-tumor activity in different types of cancer. The aim of the present study was to investigate the anti-tumor activity and molecular mechanism of ALT in ALL. Methods ALL cell lines were treated with 1, 5 and 10 μM ALT, and cell viability was assessed using an MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assays were used to measure cell apoptosis and autophagy. Additionally, western blot analysis was used to detect expression of apoptosis and autophagy related proteins. Finally, the effects of ALT on tumor growth were assessed in a BV173 xenograft nude mouse model. Results ALT inhibited the proliferation of ALL cells in a dose-dependent manner. Additionally, it was demonstrated that ALT inhibited cell proliferation, colony formation, autophagy, induced apoptosis and reduced tumor growth in vivo through upregulating the expression of adaptor related protein complex 2 subunit mu 1 (AP2M1). Moreover, the autophagy activator rapamycin, attenuated the pro-apoptotic effects of ALT on BV173 and NALM6 cell lines. Overexpression of AP2M1 decreased the expression of Beclin1 and the LC3-II/LC3-1 ratio, and increased p62 expression. Knockdown of Beclin1 increased the levels of bax, cleaved caspase 3 and cytochrome C, and decreased bcl-2 expression. Conclusions The present study demonstrated that ALT exerts anti-tumor activity through inducing apoptosis and inhibiting autophagy by upregulating AP2M1 in ALL, highlighting a potential therapeutic strategy for treatment of ALL.

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Bradykinin-related compounds as new drugs for cancer and inflammation

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y02-030 ◽

2002 ◽

Vol 80 (4) ◽

pp. 275-280 ◽

Cited By ~ 30

Author(s):

John M Stewart ◽

Lajos Gera ◽

Daniel C Chan ◽

Paul A Bunn Jr. ◽

Eunice J York ◽

...

Keyword(s):

Prostate Cancer ◽

Lung Cancer ◽

Tumor Growth ◽

Small Cell Lung Cancer ◽

Nude Mice ◽

Small Cell ◽

Small Cell Lung ◽

Related Compounds

Bradykinin (BK) (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) is an important growth factor for small-cell lung cancer (SCLC) and prostate cancer (PC). These cancers have cells of neuroendocrine origin and express receptors for a variety of neuropeptides. BK receptors are expressed on almost all lung cancer cell lines and on many PC cells. Our very potent BK antagonist B9430 (D-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-Arg) (Hyp, trans-4-hydroxy-L-proline; Igl, α-2-indanylglycine; Oic, octahydroindole-2-carboxylic acid) is a candidate anti-inflammatory drug but does not inhibit growth of SCLC or PC. When B9430 is dimerized by N-terminal cross-linking with a suberimide linker, the product B9870 is a potent growth inhibitor for SCLC both in vitro and in vivo in athymic nude mice. Daily i.p. injection at 5 mg·kg1·day1 beginning on day 8 after SCLC SHP-77 cell implantation gave 65% inhibition of tumor growth. B9870 stimulates apoptosis in SCLC by a novel "biased agonist" action. We have also developed new small mimetic antagonists. BKM-570 (F5C-OC2Y-Atmp) (F5C, pentafluorocinnamic acid; OC2Y, O-2,6-dichlorobenzyl tyrosine; Atmp, 4-amino-2,2,6,6-tetramethylpiperidine) is very potent for inhibition of SHP-77 growth in nude mice. When injected daily i.p. at 5 mg·kg1, M-570 gave 90% suppression of tumor growth. M-570 is more potent than the well-known anticancer drug cisPlatin (60% inhibition) or the recently developed SU5416 (40% inhibition) in this model. M-570 also showed activity against various other cancer cell lines in vitro (SCLC, non-SCLC, lung, prostate, colon, cervix) and inhibited growth of prostate cell line PC3 in nude mice. M-570 and related compounds evidently act in vivo through pathways other than BK receptors. These compounds have clinical potential for treatment of human lung and prostate cancers.Key words: bradykinin antagonists, cancer, inflammation, prostate cancer, small cell lung cancer.

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Eradication of established human melanoma tumors in nude mice by antibody-directed effector cells.

Journal of Experimental Medicine ◽

10.1084/jem.161.6.1315 ◽

1985 ◽

Vol 161 (6) ◽

pp. 1315-1325 ◽

Cited By ~ 44

Author(s):

G Schulz ◽

L K Staffileno ◽

R A Reisfeld ◽

G Dennert

Keyword(s):

Tumor Growth ◽

Nk Cells ◽

Nude Mice ◽

Melanoma Cells ◽

Human Melanoma ◽

Tumor Rejection ◽

Nk Activity ◽

Asialo Gm1

The simultaneous injection of monoclonal antibody 9.2.27, directed against a chondroitin sulfate proteoglycan preferentially expressed on human melanoma cells, and 2 X 10(7) mononuclear splenocytes, eradicated established, progressively growing human melanoma tumors in nude mice. Neither splenocytes nor antibody alone achieved significant tumor regression. The cells responsible for tumor elimination are most likely natural killer (NK) cells: they are present in splenocytes of T cell-deficient nude mice, and cloned cells with NK activity are able to suppress tumor growth. Moreover, splenocytes treated with anti-asialo GM1 and complement or harvested from NK-deficient C57BL/6 beige mice did not cause tumor rejection. Furthermore, treatment of BALB/c nude mice just before injection with anti-asialo GM1 antiserum, which is known to eliminate NK activity in vivo, resulted in better tumor growth. In addition, evidence is presented that cells with NK activity are probably the effectors responsible for melanoma target cell lysis in vitro: Antibody-dependent and -independent cell-mediated lysis of M21 melanoma cells was suppressed when splenocytes were preincubated with complement and antibodies specific for cell surface antigens of NK cells, i.e., anti-asialo GM1, anti-Qa5, and anti-NK1.1. Moreover, splenocytes of C57BL/6 beige mice were not able to lyse M21 cells in vitro. These results strongly support the conclusion that cells with NK activity are indeed responsible for the antibody-dependent destruction of M21 melanoma cells in vivo and in vitro.

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Ethaselen synergizes with oxaliplatin in tumor growth inhibition by inducing ROS production and inhibiting TrxR1 activity in gastric cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02052-z ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Haiyong Zhang ◽

Jing Wu ◽

Jinqiu Yuan ◽

Huafu Li ◽

Yawei Zhang ◽

...

Keyword(s):

Gastric Cancer ◽

Tumor Growth ◽

Growth Inhibition ◽

Cancer Cells ◽

Nude Mice ◽

Combined Treatment ◽

Thioredoxin Reductase ◽

Tumor Growth Inhibition ◽

Gastric Cancer Cells

Abstract Background Oxaliplatin is one of the most commonly used chemotherapeutic agent for the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Hence, it is of great significance to develop novel therapies to potentiate the anti-tumor effect and reduce the toxicity of oxaliplatin. In our previous study, we demonstrated that ethaselen (BBSKE), an inhibitor of thioredoxin reductase, effectively inhibited the growth of gastric cancer cells and promoted apoptosis in vitro. In the present study, we investigated whether BBSKE can potentiate the anti-tumor effect of oxaliplatin in gastric cancer in vivo and vitro. Methods Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells, organoid and tumor tissues was determined by using the endpoint insulin reduction assay. Western blot was used to analyze the expressions of the indicated proteins. Nude mice xenograft models were used to test the effects of BBSKE and oxaliplatin combinations on gastric cancer cell growth in vivo. In addition, we also used the combined treatment of BBSKE and oxaliplatin in three cases of gastric cancer Patient-Derived organoid (GC-PDO) to detect the anti-tumor effect. Results We found that BBSKE significantly enhanced oxaliplatin-induced growth inhibition in gastric cancer cells by inhibiting TrxR1 activity. Because of the inhibition of TrxR1 activity, BBSKE synergized with oxaliplatin to enhance the production of ROS and activate p38 and JNK signaling pathways which eventually induced apoptosis of gastric cancer cells. In vivo, we also found that BBSKE synergized with oxaliplatin to suppress the gastric cancer tumor growth in xenograft nude mice model, accompanied by the reduced TrxR1 activity. Remarkably, we found that BBSKE attenuated body weight loss evoked by oxaliplatin treatment. We also used three cases of GC-PDO and found that the combined treatment of BBSKE and oxaliplatin dramatically inhibited the growth and viability of GC-PDO with increased ROS level, decreased TrxR1 activity and enhanced apoptosis. Conclusions This study elucidates the underlying mechanisms of synergistic effect of BBSKE and oxaliplatin, and suggests that the combined treatment has potential value in gastric cancer therapy.

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Inhibition of Src and insulin/insulin-like growth factor-1 receptor (IR/IGF-1R) on tumors and bone turnover in prostate cancer (PCa) models in vivo compared with inhibition of either kinase alone.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.61 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 61-61

Author(s):

Farshid Dayyani ◽

Nila Parikh ◽

Jian H. Song ◽

John C. Araujo ◽

Joan M. Carboni ◽

...

Keyword(s):

Bone Turnover ◽

Tumor Growth ◽

Bone Turnover Markers ◽

Bone Destruction ◽

In Vivo Studies ◽

Pc3 Cells ◽

Turnover Markers ◽

Induced Apoptosis

61 Background: The Src and IGF-1R axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are clinically promising small molecule inhibitors with high potency against Src family kinases (SFK) and IR/IGF-1R, respectively. Based on a phase I/II clinical trial in which 9/19 pts treated with docetaxel + dasatinib were increased in serum IGF-1 levels after one cycle, the aim of this study was to establish potential antitumor cooperativity of inhibiting both IGF-1R and Src in experimental PCa models in vitro and in mice. Methods: Inhibition of Src and IGF-1R pathways was accomplished by pharmacologic agents (dasatinib against Src and BMS-754807 against IR/IGF-1R) as well as by shRNA, in PC3 and LNCaP cells. In vivo studies were done after orthotopic and intratibial injection of PC3 cells in nude mice. Results: SFK inhibition decreased proliferation and migration of PCa cells whereas IGF-1R blockade induced apoptosis. All anti-tumor effects were enhanced by dual blockade. IGF-1 induced phosphorylation of Akt1 and 2. Only Akt 1 phosphorylation was decreased by dasatinib; whereas Akt 1 and 2 phosphorylation were completely abrogated by the combination. Dasatinib and BMS-754807 inhibited orthotopic in vivo tumor growth of PC3 cells more potently than either inhibitor alone. Similarly, intratibial tumor growth and bone destruction was significantly reduced with the drug combination, accompanied by a decrease in serum bone turnover markers alkaline phosphatase and N-telopeptide. Conclusions: Dual inhibition of Src and IGF-1R has greater anti-tumor effect in PCa cells compared to inhibiting either alone. In the presence of IGF-1, dasatinib and BMS-754807 are necessary to inhibit IGF-1-induced phosphorylation of Akt1 and 2 in tumor cells in culture. In intratibial models, decreased bone turnover markers in serum support the concept of targeting both the epithelial and bone microenvironment. The combination of dasatinib and BMS-754807 may be a rational therapeutic approach in PCa by blocking complementary processes of tumor growth and progression.

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Indole-3-Carbinol Inhibits Nasopharyngeal Carcinoma

International Journal of Toxicology ◽

10.1177/1091581809356481 ◽

2010 ◽

Vol 29 (2) ◽

pp. 185-192 ◽

Cited By ~ 3

Author(s):

Wei Zhu ◽

Wenxue Li ◽

Guangyu Yang ◽

Quanxin Zhang ◽

Ming Li ◽

...

Keyword(s):

Superoxide Dismutase ◽

Nasopharyngeal Carcinoma ◽

Glutathione Peroxidase ◽

Tumor Growth ◽

Caspase 3 ◽

Caspase 9 ◽

Human Nasopharyngeal Carcinoma ◽

Induced Apoptosis

This study explored the effects of indole-3-carbinol on the proliferation of human nasopharyngeal carcinoma, both in vitro and in vivo, and the underlying mechanisms in inducing apoptosis of CNE1 cells. Proliferation, apoptosis, malondialdehyde, superoxide dismutase, glutathione peroxidase, expressions of caspase-9, and caspase-3 in human nasopharyngeal carcinoma cells CNE1 were examined. Indole-3-carbinol suppressed proliferation, induced apoptosis, decreased malondialdehyde level, increased the activity of superoxide dismutase and glutathione peroxidase, and up-regulated the expression of active fragments of caspase-9 and caspase-3 both in vitro and in vivo. It was concluded that indole-3-carbinol could inhibit proliferation and induce apoptosis of CNE1 cells and inhibit tumor growth in mice. Increased activity of superoxide dismutase and glutathione peroxidase and activated expression of caspase-9 and caspase-3 were also observed in indole-3-carbinol–treated tumors or tumor cells, suggesting that stress- and apoptosis-related molecules are involved in the indole-3-carbinol–induced apoptosis and inhibition of tumor growth.

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