Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro

Hahne, Jens C.; Hönig, Arnd; Meyer, Susanne; Gambaryan, Stepan; Walter, Ulrich; Wischhusen, Jörg; Häussler, S F M; Segerer, Sabine; Fujita, Naoya; Dietl, Johannes; Engel, Jörg B.

doi:10.3892/or.2012.2041

Cited by 37 publications

(48 citation statements)

References 31 publications

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“…Recent evidence by our group and others has shown that overactivation of the AKT-pathway may be associated with platinum resistance (13)(14)(15)(16)(17). It was demonstrated that parental A2780 cells become platinum resistant by overexpression of AKT and that platinum resistance in A2780cis cells can be overcome by transfection with siRNA downregulating AKT (17).…”

Section: Introductionmentioning

confidence: 96%

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Immune escape of AKT overexpressing ovarian cancer cells

Hahne

Meyer

Gambaryan

et al. 2013

International Journal of Oncology

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Abstract. Platinum-resistance is the most crucial problem for treatment of ovarian cancer. There is a clinical need for new treatment strategies which overcome platinum resistance. As survival is strongly influenced by immunological parameters, immunotherapeutic strategies appear promising. Therefore a better understanding of the interaction between ovarian tumour cells and cells of the immune system is a necessary prerequisite. In the present study we aimed to enlighten the interactions between platinum resistant and platinum sensitive ovarian cancer cells and natural-killer (NK)-cells. Modified FATAL assay was used for determining the killing efficiency of NK-cells for the parental A2780 cells and the cis-platinum resistant A2780cis human ovarian cancer cells. Expression of pro-and anti-apoptotic genes as well as ligands involved in NK-cell receptor recognition were analysed by RT-PCR and flow cytometric analysis. The efficiency of NK mediated cell lysis differs between A2780 cells and the cis-platinum-resistant A2780cis cells. A2780cis cells are less accessible for NK-cell mediated killing. Based on this observation we characterized the molecular basis for resistance mechanisms. Besides an increase in anti-apoptotic genes (especially CIAP-1 and -2) that probably render A2780cis cells more resistant against apoptosis an increased amount of soluble MICA/B seems to be responsible for the lower killing rate of platinum-resistant A2780cis cells compared to their parental A2780 cells.

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Section: Introductionmentioning

confidence: 96%

“…Preparation of cell lysates was performed as previously described (17). Membranes were probed overnight with anti-phospho-Akt antibody from Epitomics (Burlingame, CA, USA), anti-B7-H1 antibody from eBioscience (Frankfurt, Germany) or anti-β-actin antibody from Abcam (Cambridge, UK), respectively.…”

Section: Methodsmentioning

confidence: 99%

Immune escape of AKT overexpressing ovarian cancer cells

Hahne

Meyer

Gambaryan

et al. 2013

International Journal of Oncology

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“…Furthermore, the epithelialmesenchymal-transformation, an important step for tumour metastasis, has been shown to be related to AKT activation [65]. Deregulation of components of the PI3K/AKT-cascade not only contributes to ovarian cancer development and tumourigenesis but also to chemotherapeutic drug and radiation resistance as it was recently shown [4,20,[66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81]. The sensitivity of cells to radiation and 5% [137] 35-50% (m) [138,139] 20% (m) [138] Rare 3% (m) 20% (a) [140] Table 2: Frequencies of specific mutations in PIK3CA.…”

Section: Effects Of Altered Pi3k/akt/mtor-signal Transduction Pathwaymentioning

confidence: 99%

“…The cisplatinum-resistant A2780cis cell line has been developed by chronic exposure of the parental cisplatinum-sensitive A2780 cell line to increasing concentrations of the chemotherapeutic agent [94]. These cell lines are excellent models for analyzing the molecular basis for cisplatinum resistance in ovarian cancer [72][73][74][95][96][97][98]. According to these studies AKT over-expression in ovarian cancer is at least one important reason for platinum resistance in this tumour entity [61,72,99].…”

Section: Effects Of Altered Pi3k/akt/mtor-signal Transduction Pathwaymentioning

confidence: 99%

Platinum-resistance and AKT Over-expression in Ovarian Cancer

Hahne¹

2015

Int J Gynecol Clin Pract

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Ovarian cancer is among the most common cause of cancer death and ranks first in the number of deaths each year in the field of gynaecological malignancies. This is due to its late diagnosis and the development of chemoresistance. Platinum derivates, including cisplatinum and carboplatinum in combination with paclitaxel, are the first-line chemotherapeutic agents. Platinum derivates intercalates irreversibly into the DNA and creates inter-and intra-strand DNA cross-links. During cell division, platinum-DNA-adducts block the replication machinery, inducing DNA damage and apoptosis. Nearly all patients respond to first line chemotherapy before it comes later to recurrence of the disease. At time of recurrence, tumours are usually more aggressive, form metastasis in secondary tissues and acquire resistance to conventional chemotherapeutics. Drug resistance is a common problem in tumour therapy not only restricted to ovarian cancer. This is characterized by gene mutations, increased DNA repair, reduced drug efficacy and enhanced drug clearance and detoxification. Up to now the complex molecular mechanism of chemoresistance is not well understood but increasing evidence points towards AKT over-expression and alteration of the PI3K/AKT/mTOR cascade as a central mechanistic reason for this resistance.

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“…1,2) Exposure to cisplatin induces several cellular responses with consequent changes in growth regulation. Recent data suggest that the mitogen activated protein (MAP) kinase pathway, 3) the signal transducer and activator of transcription (STAT) pathway 4) and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway 5) get activated in response to cisplatin. Altered expression of intracellular signals by exposure to cytotoxic drugs may provide survival benefits to cells, leading to the development of drug resistance.…”

mentioning

confidence: 99%

Alkaloids from <i>Stephania venosa</i> as Chemo-Sensitizers in SKOV3 Ovarian Cancer Cells <i>via</i> Akt/NF-κB Signaling

Mon

Yodkeeree

Punfa

et al. 2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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Crebanine (CN), tetrahydropalmatine (THP), O-methylbulbocapnine (OMBC) and N-methyl tetrahydropalmatine (NMTHP) are isoquinoline derived natural alkaloids isolated from tubers of Stephania venosa.We investigated chemo-sensitizing effects of these alkaloids in ovarian cancer cells and evaluated underlying molecular mechanisms involved in chemo-sensitivity. Detection of cell apoptosis was evaluated by using flow cytometry. Cell viability was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Chou-Talalay median effect principle was used to evaluate potential drug interactions. Protein analyses were performed on ovarian carcinoma cells using Western blotting upon treatment with anticancer drug and alkaloids. Aporphine alkaloids, such as CN and OMBC, enhanced cisplatin sensitivity in intrinsic cisplatin resistant SKOV3 cells, but not in cisplatin sensitive A2780 cells. Protoberberine alkaloids, such as THP and NMTHP, had no synergistic effect on cisplatin sensitivity in either cell line. Chemo-sensitizing effects of CN and OMBC in SKOV3 cells were mediated via activating apoptosis-induced cell death through caspase-3, -8 and cleaved poly ADP-ribose polymerase (PARP) and via inhibiting anti-apopotic and survival protein expression, such as Bcl-xL, Baculoviral IAP repeat-containing protein 3 (cIAP-2), survivin and interleukin (IL) -6. Cisplatin stimulated protein kinase B (Akt) and nuclear factor-kappaB (NF-κB) signaling pathways, but not mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1) and signal transducer and activator of transcription 3 (STAT3) in SKOV3 cells. Akt/NF-κB signaling was blocked by CN and OMBC leading to increased sensitization to cisplatin. These findings demonstrate that CN and OMBC sensitizes SKOV3 cells to cisplatin via inhibition of Akt/NF-κB signaling and the down regulation of NF-κB mediated gene products. Our results suggest that alkaloids obtained from S. venosa could be used as chemosensitizers in ovarian cancer to sensitize and minimize the dose related toxicity of platinum-based chemotherapeutic drugs.Key words ovarian cancer; aporphine; cisplatin sensitivity; apoptosis; chemo-sensitizer Although platinum based chemotherapy is an effective treatment option for ovarian cancer patients, platinum drug resistance and the associated side effects are major limitations of the current therapeutic concepts. Cellular resistance to platinum can arise from various mechanisms related to decreased drug influx, increased DNA adduct repair, detoxification of platinum by intracellular thiols such as glutathione, alterations in intracellular signaling pathways and an increased efflux of drugs.1,2) Exposure to cisplatin induces several cellular responses with consequent changes in growth regulation. Recent data suggest that the mitogen activated protein (MAP) kinase pathway, 3) the signal transducer and activator of transcription (STAT) pathway 4) and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway 5) get activated in response t...

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Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro

Cited by 37 publications

References 31 publications

Immune escape of AKT overexpressing ovarian cancer cells

Immune escape of AKT overexpressing ovarian cancer cells

Platinum-resistance and AKT Over-expression in Ovarian Cancer

Alkaloids from <i>Stephania venosa</i> as Chemo-Sensitizers in SKOV3 Ovarian Cancer Cells <i>via</i> Akt/NF-κB Signaling

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