TRAP1, a novel antiapoptotic gene responsible for multidrug resistance in human colorectal carcinoma cells

2541 Background: TRAP1 has been recently described as a component of a mitochondrial pathway selectively up- regulated in tumor cells which antagonizes the proapoptotic activity of cyclophilin D and is responsible for maintenance of mitochondria integrity, thus favoring cell survival. Interestingly, novel TRAP1 antagonists cause sudden collapse of mitochondrial function and selective tumor cell death, suggesting that this pathway may represent a novel molecular target to improve anticancer therapy. Furthermore, we recently observed that TRAP1 is significantly up-regulated in osteosarcoma cells adapted to growth in mild oxidizing conditions and this correlates with a phenotype more resistant to H2O2-induced DNA damage and apoptosis. This evidence prompted us to investigate the role of TRAP1 as being responsible for multi-drug resistance in human colorectal cancer. Methods and Results: The evaluation of TRAP1 expression by immunoblot and quantitative RT-PCR analysis in a series of 26 human colorectal carcinomas allowed us to observe up-regulation in 17/26 tumors. Accordingly, TRAP1 protein levels were increased in HT-29 colorectal carcinoma cells resistant to 5-fluorouracil, oxaliplatin and irinotecan. Interestingly, HT-29 colorectal carcinoma and Saos-2 osteosarcoma cells transfected with TRAP1 gene exhibited a phenotype resistant to 5-fluorouracil-, oxaliplatin- and irinotecan-induced apoptosis, evaluated by MTT incorporation analysis and annexin V staining. Consistently, the transfection of a dominant negative N-terminal deletion mutant of TRAP1 as well as the inhibition of TRAP1 activity by the TRAP1 ATPase antagonist, shepherdin, increased the sensitivity to apoptosis induced by 5-fluorouracil, oxaliplatin and irinotecan in wild type HT-29 colorectal carcinoma cells and in HT-29 cells resistant to the single agents. Conclusions: These results suggest that the increased expression of TRAP1 in human colorectal carcinomas could be part of a pro-survival pathway responsible for multidrug resistance. Thus, targeting TRAP1 may represent a novel strategy to improve the efficacy of anticancer agents in colorectal cancer. No significant financial relationships to disclose.

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High Concentrations of Aspartame Induce Pro-Angiogenic Effects in Ovo and Cytotoxic Effects in HT-29 Human Colorectal Carcinoma Cells

Nutrients ◽

10.3390/nu12123600 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3600 ◽

Cited By ~ 1

Author(s):

Anca Laura Maghiari ◽

Dorina Coricovac ◽

Iulia Andreea Pinzaru ◽

Ioana Gabriela Macașoi ◽

Iasmina Marcovici ◽

...

Keyword(s):

Colorectal Cancer ◽

Colorectal Carcinoma ◽

In Vitro Cytotoxicity ◽

Scientific Data ◽

Carcinoma Cells ◽

Artificial Sweetener ◽

In Ovo ◽

Human Colorectal Carcinoma ◽

Ht 29

Aspartame (ASP), an artificial sweetener abundantly consumed in recent years in an array of dietary products, has raised some concerns in terms of toxicity, and it was even suggested a link with the risk of carcinogenesis (colorectal cancer), though the present scientific data are rather inconclusive. This study aims at investigating the potential role of aspartame in colorectal cancer by suggesting two experimental approaches: (i) an in vitro cytotoxicity screening in HT-29 human colorectal carcinoma cells based on cell viability (Alamar blue assay), cell morphology and cell migration (scratch assay) assessment and (ii) an in ovo evaluation in terms of angiogenic and irritant potential by means of the chorioallantoic membrane method (CAM). The in vitro results showed a dose-dependent cytotoxic effect, with a significant decrease of viable cells at the highest concentrations tested (15, 30 and 50 mM) and morphological cellular changes. In ovo, aspartame (15 and 30 mM) proved to have a pro-angiogenic effect and a weak irritant potential at the vascular level. These data suggest new directions of research regarding aspartame’s role in colorectal cancer.

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Aqueous Extract ofSolanum nigrumLeaves Induces Autophagy and Enhances Cytotoxicity of Cisplatin, Doxorubicin, Docetaxel, and 5-Fluorouracil in Human Colorectal Carcinoma Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/514719 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Chen-Jei Tai ◽

Chien-Kai Wang ◽

Cheng-Jeng Tai ◽

Yi-Feng Lin ◽

Chi-Shian Lin ◽

...

Keyword(s):

Colorectal Cancer ◽

Colorectal Carcinoma ◽

Aqueous Extract ◽

Tumor Suppression ◽

Drug Effect ◽

Carcinoma Cells ◽

Common Cancer ◽

Human Colorectal Carcinoma ◽

And Control ◽

Ht 29

Colorectal cancer is a common cancer worldwide, and chemotherapy is a mainstream approach for advanced and recurrent cases. Development of effective complementary drugs could help improve tumor suppression efficiency and control adverse effects from chemotherapy. The aqueous extract ofSolanum nigrumleaves (AE-SN) is an essential component in many traditional Chinese medicine formulas for treating cancer, but there is a lack of evidence verifying its tumor suppression efficacy in colorectal cancer. The purpose of this study is to evaluate the tumor suppression efficacy of AE-SN using DLD-1 and HT-29 human colorectal carcinoma cells and examine the combined drug effect when combined with the chemotherapeutic drugs cisplatin, doxorubicin, docetaxel, and 5-fluorouracil. The results indicated that AE-SN induced autophagy via microtubule-associated protein 1 light chain 3 A/B II accumulation but not caspase-3-dependent apoptosis in both cell lines. The IC50s after 48 hours of treatment were 0.541 and 0.948 mg/ml AE-SN in DLD-1 and HT-29, respectively. AE-SN also demonstrated a combined drug effect with all tested drugs by enhancing cytotoxicity in tumor cells. Our results suggest that AE-SN has potential in the development of complementary chemotherapy for colorectal cancer.

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Modulation of Cyclooxygenase-2 Expression by Apc In Ht-29 Human Colorectal Carcinoma Cells

Advances in Experimental Medicine and Biology - Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury, 5 ◽

10.1007/978-1-4615-0193-0_21 ◽

2002 ◽

pp. 127-131 ◽

Cited By ~ 1

Author(s):

Linda C. Hsi ◽

Julie Angerman-Stewart ◽

Thomas E. Eling

Keyword(s):

Colorectal Carcinoma ◽

Cyclooxygenase 2 ◽

Carcinoma Cells ◽

Human Colorectal Carcinoma ◽

Ht 29

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Bioactivity of PEGylated Graphene Oxide Nanoparticles Combined with Near-Infrared Laser Irradiation Studied in Colorectal Carcinoma Cells

Nanomaterials ◽

10.3390/nano11113061 ◽

2021 ◽

Vol 11 (11) ◽

pp. 3061

Author(s):

Natalia Krasteva ◽

Dessislava Staneva ◽

Bela Vasileva ◽

George Miloshev ◽

Milena Georgieva

Keyword(s):

Colorectal Cancer ◽

Graphene Oxide ◽

Colorectal Carcinoma ◽

Cancer Cells ◽

Laser Irradiation ◽

Molecular Mechanisms ◽

Near Infrared ◽

Carcinoma Cells ◽

Infrared Light ◽

Mitochondrial Activity

Central focus in modern anticancer nanosystems is given to certain types of nanomaterials such as graphene oxide (GO). Its functionalization with polyethylene glycol (PEG) demonstrates high delivery efficiency and controllable release of proteins, bioimaging agents, chemotherapeutics and anticancer drugs. GO–PEG has a good biological safety profile, exhibits high NIR absorbance and capacity in photothermal treatment. To investigate the bioactivity of PEGylated GO NPs in combination with NIR irradiation on colorectal cancer cells we conducted experiments that aim to reveal the molecular mechanisms of action of this nanocarrier, combined with near-infrared light (NIR) on the high invasive Colon26 and the low invasive HT29 colon cancer cell lines. During reaching cancer cells the phototoxicity of GO–PEG is modulated by NIR laser irradiation. We observed that PEGylation of GO nanoparticles has well-pronounced biocompatibility toward colorectal carcinoma cells, besides their different malignant potential and treatment times. This biocompatibility is potentiated when GO–PEG treatment is combined with NIR irradiation, especially for cells cultured and treated for 24 h. The tested bioactivity of GO–PEG in combination with NIR irradiation induced little to no damages in DNA and did not influence the mitochondrial activity. Our findings demonstrate the potential of GO–PEG-based photoactivity as a nanosystem for colorectal cancer treatment.

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Anlotinib suppresses metastasis and multidrug resistance via dual blockade of MET/ABCB1 in colorectal carcinoma cells

Journal of Cancer ◽

10.7150/jca.45618 ◽

2021 ◽

Vol 12 (7) ◽

pp. 2092-2104

Author(s):

Lin-Hai Yan ◽

Di Zhang ◽

Si-Si Mo ◽

Hao Yuan ◽

Xian-Wei Mo ◽

...

Keyword(s):

Multidrug Resistance ◽

Colorectal Carcinoma ◽

Carcinoma Cells ◽

Dual Blockade

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Pien Tze Huang Overcomes Multidrug Resistance and Epithelial-Mesenchymal Transition in Human Colorectal Carcinoma Cells via Suppression of TGF-βPathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2014/679436 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 14

Author(s):

Aling Shen ◽

Hongwei Chen ◽

Youqin Chen ◽

Jiumao Lin ◽

Wei Lin ◽

...

Keyword(s):

Multidrug Resistance ◽

Colorectal Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Carcinoma Cells ◽

Migration And Invasion ◽

Dependent Manner ◽

Mesenchymal Transition ◽

Folk Remedy ◽

Pien Tze Huang ◽

Human Colorectal Carcinoma

The traditional Chinese medicine formula Pien Tze Huang (PZH) has long been used as a folk remedy for cancer. To elucidate the mode of action of PZH against cancer, in the present study we used a 5-FU resistant human colorectal carcinoma cell line (HCT-8/5-FU) to evaluate the effects of PZH on multidrug resistance (MDR) and epithelial-mesenchymal transition (EMT) as well as the activation of TGF-βpathway. We found that PZH dose-dependently inhibited the viability of HCT-8/5-FU cells which were insensitive to treatment of 5-FU and ADM, demonstrating the ability of PZH to overcome chemoresistance. Furthermore, PZH increased the intercellular accumulation of Rhodamine-123 and downregulated the expression of ABCG2 in HCT-8/5-FU cells. In addition, drug resistance induced the process of EMT in HCT-8 cells as evidenced by EMT-related morphological changes and alteration in the expression of EMT-regulatory factors, which however was neutralized by PZH treatment. Moreover, PZH inhibited MDR/EMT-enhanced migration and invasion capabilities of HCT-8 cells in a dose-dependent manner and suppressed MDR-induced activation of TGF-βsignaling in HCT-8/5-FU cells. Taken together, our study suggests that PZH can effectively overcome MDR and inhibit EMT in human colorectal carcinoma cells via suppression of the TGF-βpathway.

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p53 Mutants Have Selective Dominant-Negative Effects on Apoptosis but Not Growth Arrest in Human Cancer Cell Lines

Molecular and Cellular Biology ◽

10.1128/mcb.20.3.770-778.2000 ◽

2000 ◽

Vol 20 (3) ◽

pp. 770-778 ◽

Cited By ~ 39

Author(s):

Oscar N. Aurelio ◽

Xiao-Tang Kong ◽

Swati Gupta ◽

Eric J. Stanbridge

Keyword(s):

Human Cancer ◽

Growth Arrest ◽

Carcinoma Cells ◽

Dominant Negative ◽

Wild Type ◽

Osteosarcoma Cells ◽

Negative Effects ◽

Human Cancer Cell Lines ◽

Lung Carcinoma Cells ◽

Apoptotic Pathways

ABSTRACT A bidirectional expression vector that allowed equal transcription of cloned wild-type and mutant p53 cDNAs from the same vector was developed. The vector was transfected into CaLu 6 lung carcinoma cells or Saos-2 osteosarcoma cells. All p53 mutants examined were recessive to wild-type p53 transactivation ofp21WAF1/CIP1 but dominant-negative for transactivation of Bax. An examination of effects on growth arrest and apoptotic pathways indicated that all mutants were recessive to wild type for growth arrest but only three of seven mutants were dominant negative for induction of apoptosis.

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Effects of Polar Steroids from the Starfish Patiria (=Asterina) pectinifera in Combination with X-Ray Radiation on Colony Formation and Apoptosis Induction of Human Colorectal Carcinoma Cells

Molecules ◽

10.3390/molecules24173154 ◽

2019 ◽

Vol 24 (17) ◽

pp. 3154 ◽

Cited By ~ 3

Author(s):

Olesya S. Malyarenko ◽

Timofey V. Malyarenko ◽

Alla A. Kicha ◽

Natalia V. Ivanchina ◽

Svetlana P. Ermakova

Keyword(s):

Colorectal Carcinoma ◽

Colony Formation ◽

Soft Agar ◽

Carcinoma Cells ◽

Rational Approach ◽

Apoptosis Induction ◽

Dna Comet Assay ◽

X Ray ◽

Asterina Pectinifera ◽

Ht 29

Despite significant advances in the understanding, prevention, and treatment of cancer, the disease continues to affect millions of people worldwide. Chemoradiation therapy is a rational approach that has already proven beneficial for several malignancies. However, the existence of toxicity to normal tissue is a serious limitation of this treatment modality. The aim of the present study is to investigate the ability of polar steroids from starfish Patiria (=Asterina) pectinifera to enhance the efficacy of radiation therapy in colorectal carcinoma cells. The cytotoxic activity of polar steroids and X-ray radiation against DLD-1, HCT 116, and HT-29 cells was determined by an MTS assay. The effect of compounds, X-ray, and their combination on colony formation was studied using the soft agar method. The molecular mechanism of the radiosensitizing activity of asterosaponin P1 was elucidated by western blotting and the DNA comet assay. Polar steroids inhibited colony formation in the tested cells, and to a greater extent in HT-29 cells. Asterosaponin P1 enhanced the efficacy of radiation and, as a result, reduced the number and size of the colonies of colorectal cancer cells. The radiosensitizing activity of asterosaponin P1 was realized by apoptosis induction through the regulation of anti- and pro-apoptotic protein expression followed by caspase activation and DNA degradation.

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