scholarly journals AT101 [(-)-Gossypol] Selectively Inhibits MCL1 and Sensitizes Carcinoma to BH3 Mimetics by Inducing and Stabilizing NOXA

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2298
Author(s):  
David J. Mallick ◽  
Alan Eastman
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Bh3 Mimetics ◽  
Bcl2 Family ◽  
Unfolded Protein ◽  
Carcinoma Cell Lines ◽  
Apoptotic Protein ◽  
The Unfolded Protein Response ◽  
Direct Inhibitors

Anti-apoptotic BCL2 proteins are important targets for cancer therapy as cancers depend on their activity for survival. Direct inhibitors of MCL1 have entered clinical trials, although their efficacy may be limited by toxicity. An alternative approach may be to induce the pro-apoptotic protein NOXA which selectively inhibits MCL1 in cells. Many compounds originally proposed as inhibitors of the BCL2 family were subsequently found to induce the pro-apoptotic protein NOXA through the unfolded protein response. In the present study, we compared various putative BH3 mimetics across a panel of carcinoma cell lines and measured expression of NOXA protein and mRNA, as well as the kinetics of NOXA induction. We found that AT101 [(-)-gossypol] induces high levels of NOXA in carcinoma cell lines yet cells survive. When combined with an appropriate BCL2 or BCL-XL inhibitor, NOXA-dependent sensitization occurs. NOXA protein continues to accumulate for many hours after AT101 is removed, providing a window for administering these combinations. As MCL1 promotes drug resistance and overall survival, we propose that NOXA induction is an alternative therapeutic strategy to target MCL1 and either kill cancer cells that are dependent on MCL1 or sensitize cancer cells to other BCL2 inhibitors.

Characterization of stem cell–like cancer cells in immune-competent mice

Blood ◽  
2006 ◽  
Vol 108 (12) ◽  
pp. 3906-3912 ◽  
Author(s):  
Jorg A. Kruger ◽  
Charles D. Kaplan ◽  
Yunping Luo ◽  
He Zhou ◽  
Dorothy Markowitz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Cells ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Side Population ◽  
Carcinoma Cell Lines ◽  
Tumorigenic Potential ◽  
4T1 Cells

AbstractRecently, the cancer stem cell hypothesis has gained significant recognition as the descriptor of tumorigenesis. Although previous studies relied on transplanting human or rat tumor cells into immunecompromised mice, our study used the Hoechst 33342 dye–based side population (SP) technique to isolate and transplant stem cell–like cancer cells (SCLCCs) from the 4T1 and NXS2 murine carcinoma cell lines into the immune-competent microenvironment of syngeneic mice. 4T1 cells displayed an SP of 2% with a Sca-1highc-Kit–CD45– phenotype, whereas NXS2 cells contained an SP of 0.2% with a Sca-1highCD24highc-Kit–CD45–GD high2 phenotype. Reverse transcription–polymerase chain reaction (RT-PCR) further revealed up-regulation in SP cells of ABCG2, Sca-1, Wnt-1, and TGF-β2. Additionally, 4T1 and NXS2 SP cells exhibited increased resistance to chemotherapy, and 4T1 SP cells also showed an increased ability to efflux doxorubicin, which correlated with a selective increase in the percentage of SP cells found in the tumors of doxorubicin-treated mice. Most importantly, SP cells showed a markedly higher repopulation and tumorigenic potential in vivo, which correlated with an increased number of cells in the SP compartment of SP-derived tumors. Taken together, these results show that we successfully characterized SCLCCs from 2 murine carcinoma cell lines in the immune-competent microenvironment of syngeneic mice.

scholarly journals Different Induction of GRP78 and CHOP as a Predictor of Sensitivity to Proteasome Inhibitors in Thyroid Cancer Cells

Endocrinology ◽  
2007 ◽  
Vol 148 (7) ◽  
pp. 3258-3270 ◽  
Author(s):  
Hua-Qin Wang ◽  
Zhen-Xian Du ◽  
Hai-Yan Zhang ◽  
Da-Xin Gao
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Sensitive Cell ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Thyroid Cancer Cells

Proteasome inhibitors represent a novel class of antitumor agents with preclinical and clinical evidence of activity against hematological malignancies and solid tumors. Emerging lines of evidence suggest that the unfolded protein response is implicated in proteasome inhibitors-induced apoptosis. Glucose-regulated protein 78 kDa (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) as part of the unfolded protein response play critical roles in cell survival or death. Here we demonstrate that induction of GRP78 and CHOP are differently regulated upon proteasome inhibition in different thyroid cancer cell lines, and GRP78 levels as well as preferential induction of GRP78 or CHOP appears to be involved in the responsiveness. Insensitive ARO, 8305C, and 8505C cell lines inherently express relatively high levels of GRP78 compared with sensitive cell lines, and its levels are further up-regulated upon treatment with proteasome inhibitors. CHOP levels are dramatically induced in sensitive cell lines until 24 h after proteasome inhibition. On the other hand, only a slight increase is observed at 4 h in insensitive cell lines, and this increase is unable to be detected after 8 h. Insensitive cells are sensitized to proteasome inhibition by suppression of GRP78. Furthermore, suppression of CHOP induction or overexpression of GRP78 partially prevents proteasome inhibition-mediated cell death. Our study indicates a molecular mechanism by which the sensitivity of thyroid cancer cells is regulated by the level of GRP78 as well as preferential induction of GRP78 or CHOP upon treatment with proteasome inhibitors. Our experiments therefore suggest a novel approach toward sensitization of thyroid cancer cells to proteasome inhibitors.

scholarly journals DNAzyme as an efficient tool to modulate invasiveness of human carcinoma cells.

2010 ◽  
Vol 57 (3) ◽  
Author(s):  
Magdalena Wiktorska ◽  
Izabela Papiewska-Pająk ◽  
Andrzej Okruszek ◽  
Izabela Sacewicz-Hofman ◽  
Jolanta Niewiarowska
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Carcinoma Cells ◽  
Integrin Subunit ◽  
Β1 Integrin ◽  
Adhesive Properties ◽  
Human Carcinoma ◽  
Carcinoma Cell Lines ◽  
Β1 Integrins

In this study we evaluated efficiency of DNAzymes to modulate motility of cancer cells, an important factor in the progression and metastasis of cancers. For this purpose we targeted β1 integrins that are predominant adhesive receptors in various carcinoma cell lines (CX1.1, HT29, LOVO, LS180, PC-3). To evaluate invasiveness of cancer cells, we used a transwell migration assay that allowed analyzing chemotactic migration of colon carcinoma cell lines across an ECM-coated membrane. Their adhesive properties were also characterized by the analysis of adhesion to fibronectin, laminin and collagen. In addition, the expression of major integrin subunits, selected intact β1 integrins, and other adhesive receptors (ICAM, E-selectin, uPAR) was analyzed by flow cytometry. Inhibition of β1 integrin expression by DNAzyme to β1 mRNA almost abolished the invasiveness of the CX1.1, HT29, LS180, LOVO and PC-3 cells in vitro. These data show that DNAzymes to β1 integrin subunit can be used to inhibit invasiveness of carcinoma cells.

Peroxisome proliferator–activated receptor-γ agonists cause growth arrest and apoptosis in human ovarian carcinoma cell lines

2007 ◽  
Vol 17 (2) ◽  
pp. 418-425 ◽  
Author(s):  
Y.-C. Yang ◽  
Y.-P. Tsao ◽  
T.-C. Ho ◽  
I.-P Choung
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Ovarian Cancer Cells ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Carcinoma Cell Lines ◽  
Pparγ Agonists ◽  
Human Ovarian Carcinoma

Peroxisome proliferator–activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. PPARγ agonists inhibit the growth of many types of cancers. To our knowledge, the effect of PPARγ agonist on ovarian tumors is not reported. In this study, we used two human ovarian carcinoma cell lines (ES-2 and PA-1) to examine the effects of the PPARγ agonists troglitazone (TGZ) and ciglitazone (CGZ) on cell survival. CGZ and TGZ inhibited viability in a dose-dependent manner in both types of ovarian cancer cells. The agonists also decreased cellular proliferation in association with an increase in the number of cells arrested in the G0/G1 phase of the cell cycle. Moreover, they increased apoptosis while increasing caspase-3 activity. Incubation of both the cell lines with the PPARγ agonists led to upregulated PPARγ expression. This effect appeared to be PPARγ independent because the PPARγ antagonist GW9662 did not reverse it. Along with the induction of apoptosis in ovarian cancer cells, protein expression levels of p53 and Bax markedly increased in response to the PPARγ agonists. Our results demonstrated that PPARγ agonists inhibited the viability of human ovarian cancer cells, at least partly by inducing apoptosis. As a result, these agonists may serve as future drugs for the prevention and treatment of ovarian cancer

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