Combination of AT-101/cisplatin overcomes chemoresistance by inducing apoptosis and modulating epigenetics in human ovarian cancer cells

Karaca, Burçak; Atmaca, Harika; Bozkurt, Emir; Kısım, Aslı; Uzunoğlu, Selim; Karabulut, Bülent; Sezgin, Canfeza; Şanlı, Ulus Ali; Uslu, Rüçhan

doi:10.1007/s11033-012-2469-z

Cited by 39 publications

(27 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results indicate that DNA methylation involves the regulation of multidrug resistance in ovarian cancer through apoptosis. The latter finding is in good agreement with that of previous studies (86,87). As shown in Table I, there are at least seven genes, including PTEN, BLU and UCHL1, that participate in the regulation of multidrug resistance in ovarian cancer through cell apoptosis.…”

Section: Discussionsupporting

confidence: 92%

Integration and bioinformatics analysis of DNA-methylated genes associated with drug resistance in ovarian cancer

et al. 2016

View full text Add to dashboard Cite

Abstract.The main obstacle to the successful treatment of ovarian cancer is the development of drug resistance to combined chemotherapy. Among all the factors associated with drug resistance, DNA methylation apparently plays a critical role. In this study, we performed an integrative analysis of the 26 DNA-methylated genes associated with drug resistance in ovarian cancer, and the genes were further evaluated by comprehensive bioinformatics analysis including gene/protein interaction, biological process enrichment and annotation. The results from the protein interaction analyses revealed that at least 20 of these 26 methylated genes are present in the protein interaction network, indicating that they interact with each other, have a correlation in function, and may participate as a whole in the regulation of ovarian cancer drug resistance. There is a direct interaction between the phosphatase and tensin homolog (PTEN) gene and at least half of the other genes, indicating that PTEN may possess core regulatory functions among these genes. Biological process enrichment and annotation demonstrated that most of these methylated genes were significantly associated with apoptosis, which is possibly an essential way for these genes to be involved in the regulation of multidrug resistance in ovarian cancer. In addition, a comprehensive analysis of clinical factors revealed that the methylation level of genes that are associated with the regulation of drug resistance in ovarian cancer was significantly correlated with the prognosis of ovarian cancer. Overall, this study preliminarily explains the potential correlation between the genes with DNA methylation and drug resistance in ovarian cancer. This finding has significance for our understanding of the regulation of resistant ovarian cancer by methylated genes, the treatment of ovarian cancer, and improvement of the prognosis of ovarian cancer. IntroductionOvarian cancer is a malignant tumour posing a serious threat to women's health. As the main type of ovarian cancer, ovarian epithelial carcinoma accounts for 85-90% of all ovarian cancers. The mortality rate of ovarian epithelial carcinoma ranks first among all female reproductive tract malignancies. Approximately 70% of ovarian cancer patients are in the late stage when diagnosed. Most of these tumours easily develop drug resistance in the course of post-surgery chemotherapy; therefore, the therapeutic effect is greatly reduced, leading to a survival rate of just 30% for ovarian cancer (1). Therefore, multidrug resistance is the main cause of ovarian cancer chemotherapy failure. Studies have demonstrated that multidrug resistance is the result of multiple genes or proteins and a multistep process, or cross-reactivity of multiple factors. Multidrug resistance involves several different regulatory mechanisms, and epigenetic regulation is one of the significant regulatory mechanisms in the development of ovarian cancer multidrug resistance (2). Epigenetic modification is a heritable change in gene expression without a DNA...

show abstract

Section: Discussionsupporting

confidence: 92%

Integration and bioinformatics analysis of DNA-methylated genes associated with drug resistance in ovarian cancer

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Its role has been documented in prostate cancer for paclitaxel/docetaxel resistance [41] as well as in renal [42], and melanoma [43],breast tumor cells [9,44]. Most significantly, sCLU expression is documented to lead to broad-based resistance to other unrelated chemotherapeutic agents such as doxorubicin [9,45], DDP [9,45,46], and etoposide [47]. …”

Section: Discussionmentioning

confidence: 99%

Secreted Clusterin Gene Silencing Enhances Chemosensitivity of A549 Cells to Cisplatin Through AKT and ERK1/2 Pathwaysin Vitro

Zhang¹,

Zhang²,

Liu³

et al. 2014

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Several studies have shown secreted clusterin (sCLU) silencing directed against sCLU mRNA in sCLU-rich lung cancer cell lines sensitized cells to chemotherapy. However, the molecular mechanisms underlying the effect of sCLU silencing on lung cancer cell chemosensitivity is not known. In the present study, we aimed to determine that vector expressing short hairpin RNA against sCLU RNA (sCLU-shRNA) enhances the chemosensitivity in human small cell lung cancer A549 cells in vitro by inhibition of phosphorylated ERK1/2 (p-ERK1/2) and Akt (p-Akt). Methods: The pCDNA3.1-sCLU and control scrambled pCDNA3.1 plasmid was constructed. We investigated the effects of sCLU overexpression by pCDNA3.1-sCLU transfection on chemosensitivity to cisplatin (DDP) in A549 cells in vitro. We down-regulated sCLU expression by short hairpin RNA against sCLU RNA (sCLU-shRNA) and investigated the effects on chemosensitivity to DDP in A549 cells and A549^DDPin vitro. In order to confirm the correlation between sCLU and AKT and ERK1/2 signals, cells were treated with wortmannin and U0126. Results: We found the chemotherapeutic agent DDP activated sCLU. Overexpression of sCLU increased cellular DDP chemoresistance in the A549^DDP and pCDNA3. 1-sCLU transfected A549 cells via inhibition DDP-induced apoptosis. Whereas sCLU knockdown induced chemosensitization in the S549 and A549^DDP cells via increase of DDP-induced apoptosis. sCLU overexpression activated pAKT Ser⁴⁷³ and pERK1/2^{Thr202/Tyr204}, and vice versa. Inhibition of pAKT Ser⁴⁷³ and pERK1/2^{Thr202/Tyr204} was sufficient to induce significant recover y in chemosensitivity to DDP in A549^DDP in the presence of sCLU overexpression. The DDP activated sCLU, which directly regulated pAKT and pERK1/2. Conclusions: This novel finding suggests that therapies directed against sCLU and its downstream signaling targets pAKT and pERK1/2 may have the potential to enhance the efficacy of DDP-based chemotherapy.

show abstract

“…[45][46][47] Modulation of DNA methylation affects the DAPK1 expression in SCC cells upon cisplatin exposure Accumulating evidence shows that promoter DNA hypermethylation of various genes involved in cell cycle arrest or apoptosis leads to their epigenetic repression and subsequently to chemoresistance of tumor cells to anticancer drugs. [48][49][50][51] Several DNA methyltransferases, DNMT1, DNMT3A, and DNMT3B, are involved in the addition of methyl groups to the 5′-cytosine at the CpG islands within the specific promoter DNA sequences, subsequently repressing the transcription of these genes. DNMT1 preserves the methylation DNA patterns throughout each cell division, while DNMT3A and 3B transfer a methyl group to unmethylated DNA sequences.…”

Section: P-δnp63α-dependent Epi-micrornas Modulate the Expression Of mentioning

confidence: 99%

Phospho-ΔNp63α/microRNA network modulates epigenetic regulatory enzymes in squamous cell carcinomas

Ratovitski

2014

Cell Cycle

View full text Add to dashboard Cite

Combination of AT-101/cisplatin overcomes chemoresistance by inducing apoptosis and modulating epigenetics in human ovarian cancer cells

Cited by 39 publications

References 33 publications

Integration and bioinformatics analysis of DNA-methylated genes associated with drug resistance in ovarian cancer

Integration and bioinformatics analysis of DNA-methylated genes associated with drug resistance in ovarian cancer

Secreted Clusterin Gene Silencing Enhances Chemosensitivity of A549 Cells to Cisplatin Through AKT and ERK1/2 Pathwaysin Vitro

Phospho-ΔNp63α/microRNA network modulates epigenetic regulatory enzymes in squamous cell carcinomas

Contact Info

Product

Resources

About