Natural resistance to apoptosis correlates with resistance to chemotherapy in colorectal cancer cells

Zhang, Yan; Yuan, Jia; Zhang, Hong Yan; Simayi, Dilixia; Li, Pin Dong; Wang, Ying Hong; Li, Feng; Zhang, Wen Jie

doi:10.1007/s10238-011-0146-5

Cited by 25 publications

(19 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, we demonstrated the usefulness of Ad-Vpr in inhibition of colorectal cancer cell viability, further validating previous in vivo and in vitro studies on different human cancer (6)(7)(8)(9). The advantage of Ad-Vpr is that Vpr is a 96 amino acid 14-kDa protein and induces G2 cell cycle arrest and apoptosis in proliferating cells (6)(7)(8)(9). Our current study also confirmed the effects of Vpr in multidrug-resistant colorectal cancer cells.…”

Section: Discussionsupporting

confidence: 87%

HIV-1 viral protein R (Vpr) induction of apoptosis and cell cycle arrest in multidrug-resistant colorectal cancer cells

Zhang

Wang

et al. 2012

Oncol Rep

View full text Add to dashboard Cite

Abstract. Colorectal cancer is a significant health problem, and the advanced stages of the disease have a low response rate to chemotherapy and easily acquire chemoresistance. HIV-1 viral protein R (Vpr) has been shown to possess inhibitory effects on various malignant cells in vivo and in vitro. In this study, an Ad-Vpr construct was used to infect the multidrug-resistant human colorectal cancer HCT-8/5-FU(MDR) cell line in vitro for cell viability, apoptosis, gene expression and gene activity using the MTT, flow cytometry, immunoblotting and gel shift assays, respectively. The data showed that Ad-Vpr significantly reduced HCT-8/5-FU(MDR) cell viability in a dose-and time-dependent manner. Ad-Vpr infection promoted HCT-8/5-FU(MDR) cells to undergo apoptosis and to arrest at the G2 phase of the cell cycle. The G2 cell cycle protein Cyclin B1 accumulated in the cells after Ad-Vpr infection. Furthermore, Ad-Vpr induced activation of caspase-3 and -9, but not caspase-8, in HCT-8/5-FU(MDR) cells. Ad-Vpr suppressed expression of the Bcl-xl protein, but upregulated Bax expression and cytochrome c release from the mitochondria in HCT-8/5-FU(MDR) cells. Ad-Vpr infection also resulted in a time-dependent decrease in nuclear translocation of NF-κB/p65 protein and p65 DNA-binding activity in HCT-8/5-FU(MDR) cells. The data from the current study provide mechanistic insights into understanding the molecular basis and utility of Ad-Vpr as a novel anticancer agent for multidrug resistance in human colorectal cancer. IntroductionColorectal cancer is a significant health problem in the world, and is the third most common cancer in women and the fourth most common in men. More than half a million patients with colorectal cancer die of the disease annually worldwide (1,2). To date, surgical intervention is the most effective tool to cure colorectal cancer, whereas chemotherapy is another important means to treat colorectal cancer, especially for advanced staged disease. In those patients, chemotherapy appears to be the only therapeutic modality and offers some benefit. For chemotherapy, 5-fluorouracil (5-FU)-based regimens are the most common choice for patients. The combination of 5-FU with irinotecan and oxaliplatin has significantly improved the response rate of colorectal cancer patients. Additionally, combination regimens of 5-FU with irinotecan have been evaluated as the first-line therapeutic selection for advanced colorectal cancer with a response rate of 30-50% and an overall survival of 14-20 months (3,4). However, the response rate for these advanced targeted therapies and third-generation chemotherapies remains low (5). The reason may be due to innate and acquired chemoresistance (6) of colorectal cancer, which often leads to relapse and poor patient prognosis. Thus, a more aggressive and effective therapy to control colorectal cancer is imperative.To this end, our research focuses on the viral protein R (Vpr), which is an accessory protein and plays an important role in the regulation of nuclear import of the HIV-1 ...

show abstract

Section: Discussionsupporting

confidence: 87%

HIV-1 viral protein R (Vpr) induction of apoptosis and cell cycle arrest in multidrug-resistant colorectal cancer cells

Zhang

Wang

et al. 2012

Oncol Rep

View full text Add to dashboard Cite

show abstract

“…Gamrekelashvili et al (19) reported that necrosis may inhibit cancer recurrence by acquiring tolerance without inducing tumor immunity such as apoptosis. In our study, DHL-TauZnNa showed an antiproliferative effect associated with autophagy in HT-29 cells, which exhibit resistance to apoptosis and chemoresistance (20), suggesting that DHL-TauZnNa may be a new therapeutic strategy against cancer cells with resistance to apoptosis. In the present study, DHL-TauZnNa induced G2/M-phase cell cycle arrest.…”

Section: Discussionmentioning

confidence: 53%

DHL-TauZnNa, a newly synthesized α-lipoic acid derivative, induces autophagy in human colorectal cancer cells

et al. 2013

View full text Add to dashboard Cite

Abstract. In recent years, several antioxidant substances have been found to have an antiproliferative effect on various types of carcinomas. α-lipoic acid (ALA) induces apoptosis in several types of cancer cell lines, but it is difficult to apply α-lipoic acid in clinical use as it is easily oxidized and unstable. Recently, we succeeded in synthesizing the α-lipoic acid derivative sodium N-[6,8-dimercaptooctanoyl]-2-aminoethanesulfonate zinc complex (DHL-TauZnNa), which has highly stable antioxidant effects. We investigated whether DHL-TauZnNa elicits its antiproliferative effects in vivo and in vitro by inducing apoptosis, autophagy or cell cycle arrest, and we analyzed the expression of proteins related to these phenomena and their phosphorylation in HT-29 human colon cancer cells. Subcutaneously administered DHL-TauZnNa treatment applied daily for 41 days significantly inhibited tumor growth by 43% in a xenograft mouse model (P=0.0271). DHL-TauZnNa significantly reduced cell viability over that of controls in the trypan-blue exclusion test in a time-and dose-dependent manner (P<0.05). DHL-TauZnNa increased the proportion of cells in S phase and decreased that of cells in G0/G1 phase in the cell cycle analysis of HT-29 cells. Although DHL-TauZnNa did not increase caspase-3/7 activity and DNA fragmentation in flow cytometry analysis, it increased the expression of microtubule-associated protein light chain 3-II. Autophagosomes and autolysosomes were observed by electron microscopy in the cytoplasm of HT-29 cells treated with DHL-TauZnNa. These results suggest that DHL-TauZnNa inhibited the proliferation of HT-29 cells through the mechanisms of G2/M cell cycle arrest and autophagy but not that of apoptosis. The newly synthesized ALA derivative DHL-TauZnNa may be expected to become a novel cancer therapeutic strategy through its induction of autophagy.

show abstract

“…This severity of colorectal cancer is probably due to development of metastasis and chemoresistance of colorectal cancer cells (Gallagher and Kemeny, 2010;Zhang et al, 2012). Recent data revealed promising potential for drugs initially designed for treatment of inflammation and infection in therapy of cancers whose tumorigenesis is related to the above-mentioned processes.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Nitric Oxide-Modified Drugs in Colon Cancer Cells

Mojić¹,

Mijatović²,

Maksimović‐Ivanić³

et al. 2012

Mol Pharmacol

View full text Add to dashboard Cite

We have examined the influence of the nitric oxide (NO)-modified anti-inflammatory drug (S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid (VGX-1027) named GIT-27NO or the NOmodified antiviral drug saquinavir (Saq) named Saq-NO on two colon cancer cell lines, mouse CT26CL25 and human HCT116. The effects of the drugs on cell viability, apoptosis, proliferation, and metastatic potential were analyzed. The release of NO and oxygen and nitrogen species was also determined. The efficacy of the drugs was evaluated in vivo in BALB/c mice injected with CT26CL25 cells. Both agents suppressed the growth of colon cancer cells in vitro and reduced tumor volume in syngeneic BALB/c mice. However, their mechanisms of action were different because GIT-27NO released larger amounts of nitrite than Saq-NO in cell cultures and its antitumor action depended on the intracellular NO release inside the cells. On the contrary, Saq-NO released barely detectable amounts of NO and its antitumor action was NO-independent. In fact, cotreatment with an NO-peroxynitrite scavenger revealed that GIT-27NO but not Saq-NO acts through peroxynitrite-mediated cell destruction. At the cellular level, GIT-27NO prevalently induced proapoptotic signals followed by caspase-dependent apoptosis. In contrast, Saq-NO blocked cell proliferation, changed the adhesive, migratory, and invasive properties of the cells, and decreased metastatic potential in vivo. In conclusion, differences in NO release and oxidative stress generation between GIT-27NO and Saq-NO resulted in different mechanisms that caused cell death.

show abstract

Natural resistance to apoptosis correlates with resistance to chemotherapy in colorectal cancer cells

Cited by 25 publications

References 24 publications

HIV-1 viral protein R (Vpr) induction of apoptosis and cell cycle arrest in multidrug-resistant colorectal cancer cells

HIV-1 viral protein R (Vpr) induction of apoptosis and cell cycle arrest in multidrug-resistant colorectal cancer cells

DHL-TauZnNa, a newly synthesized α-lipoic acid derivative, induces autophagy in human colorectal cancer cells

Therapeutic Potential of Nitric Oxide-Modified Drugs in Colon Cancer Cells

Contact Info

Product

Resources

About