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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 657-662

Octreotide reverses the resistance of A2780/Pacliaxel ovarian cancer cell line to paclitaxel chemotherapy in vitro


Department of Obstetrics and Gynecology, Zhongda Hospital, Southeast University, Nanjing, China

Date of Web Publication25-Jul-2016

Correspondence Address:
Yang Shen
Department of Obstetrics and Gynecology, Zhongda Hospital, Southeast University, Nanjing - 210 009
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.151861

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 > Abstract 


Objective: To study the anti-tumor effects of octreotide on A2780/Taxol ovarian cancer cells in vitro, and further explore its potential molecular mechanism.
Materials and Methods: Immunocytochemistry was performed to determine the expression of SSTR2 on A2780/Taxol cells. Octreotide at different concentrations (0, 1.25, 2.5, 5.0, 10.0, and 20.0 nmol/ml) were administrated to A2780/Taxol cells in vitro. CCK-8 assay was used to measure the effects on cell proliferation, and the cytometry of octreotide determined the cell apoptosis. The expressions of SSTR2 MDR1, and vascular endothelial growth factor (VEGF) messenger ribonucleic acid (mRNA) were investigated by quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay and the expressions of the above protein were investigated after A2780/Taxol was treated with octreotide for 48 hours by western blot in vitro.
Results: Positive expression of SSTR2 was observed on the membrane of A2780/Taxol cells. The proliferation of A2780/Taxol cells was gradually inhibited with increasing octreotide concentration in a concentration-dependent and time-dependent manner. Meanwhile, flow cytometry data demonstrated the octreotide-induced cell apoptosis. The results of SSTR2 mRNA suggested that there was no significant difference between each concentration group of octreotide (P > 0.05). Compared with the control group, both the MDR1 and VEGF mRNA decreased in a dose-dependent manner following 48 hours of treatment of octreotide (P < 0.05). The results of western blot showed that octreotide decreased the expressions of SSTR2, MDR1, and VEGF protein in a dose-dependent manner (P < 0.05).
Conclusions: Octreotide significantly inhibits ovarian cancer's proliferation and promotes its apoptosis via the cell surface expression of SSTR2. It could be used as a new targeted drug for treatment of ovarian cancer.

Keywords: Octreotide, ovarian cancer, paclitaxel, resistance, somatostatin


How to cite this article:
Shen Y, Zhang XY, Chen X, Ren ML, Cai YL. Octreotide reverses the resistance of A2780/Pacliaxel ovarian cancer cell line to paclitaxel chemotherapy in vitro. J Can Res Ther 2016;12:657-62

How to cite this URL:
Shen Y, Zhang XY, Chen X, Ren ML, Cai YL. Octreotide reverses the resistance of A2780/Pacliaxel ovarian cancer cell line to paclitaxel chemotherapy in vitro. J Can Res Ther [serial online] 2016 [cited 2019 Sep 18];12:657-62. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/657/151861




 > Introduction Top


Ovarian cancer is a health-threatening tumor disease which has been brought to the forefront. Approximately 23,000 women are diagnosed with ovarian cancer each year, and the 5-year survival rate is 30%.[1],[2] Today platinum combined with paclitaxel remains the first-line chemotherapy in the treatment of ovarian cancer. Unfortunately, while most patients initially respond to this combination chemotherapy, a majority of the patients (up to 75%) will eventually relapse within 18 months, many with drug-resistant disease,[3] and the efficacy of second-line chemotherapy is limited,[4] Paclitaxel is a compound isolated from the Taxus and has an extensive anti-tumor effect. As the first-line chemotherapy for ovarian cancer, paclitaxel could bind to the tubulin of cancer cell, which makes microtubule polymerize into a stable substance, prevents microtubule from depolymerization and makes the cell proliferation arrest in G2/M phase, thus inhibits the proliferation of tumor cells. Like most chemotherapy drugs, the resistance to paclitaxel limits the clinical application of paclitaxel in a certain extent.

Mutiple drug resistance gene-1 (MDR1) over-expression of which is one of the important mechanism to cause PTX MDR1. Over-expression of MDR1 could cause over-expression of its code p-gp, and which could outlet the drug in cell and decrease the concentration of drug density. Vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor (VEGF), VEGF is an important growth factor for improving the growth of vascular and plays a key role in the growth of tumor vascular. Akiyama mentioned that VEGF, which is released from tumor tissue, could activate VEGFR2 and Akt to increase the expression of MDR1.

Therefore, it is important to explore new types of drugs that could reverse chemotherapy resistance and enhance sensitivity to chemotherapy drugs. Somatostatin (SST) is a cyclic polypeptide hormone, which is scattered in most human organs and tissues. SST has a broad range of cellular functions such as inhibition, cell proliferation, and cell survival.[5],[6] Natural SST is limited in clinical applications because of its low selectivity and short half-life. However, somatostatin analogue (SSTA) is widely used in the clinic and has been shown to have more powerful effects and a longer half-life. It has been shown that SSTA not only inhibits the proliferation of neuroendocrine tumors in vitro but also inhibits solid tumor growth in vivo.[6],[7],[8],[9]

However, whether SST and SSTA could enhance the sensitivity of ovarian cancer remains unclear. This study investigated the function and mechanism of octreotide, one type of octapeptide SSTA, on paclitaxel-resistant A2780/Taxol ovarian cancer cell growth and resistance reversal. The paper provides a new understanding of the clinical treatment of ovarian cancer and drug resistance reversal.


 > Materials and Methods Top


Immunocytochemistry

Immunocytochemistry was performed to evaluate the possible expression of SSTR2 in A2780/Taxol cells. The cells were cultured on coverslips under their respective conditions in a six-well plate, fixed in 4% paraformaldehyde for 30 minutes, washed with phosphate buffered saline (PBS) for 5 minutes, and then permeabilized with Triton X-100 (Sigma-Aldrich). The cells were incubated with 10% goat serum for 20 minutes; and in the primary rabbit monoclonal antibody, anti-SSTR2 (1:100; Abcam) overnight at 4°C, in a humidified chamber. Horseradish peroxidase (HRP)-labeled secondary antibody was applied for 30 minutes after washed with PBS. Every cover slip was immersed in freshly prepared diaminobenzidine (DAB) solution and was rinsed twice with tap water till the cells in the slip turn brown. Cells were counterstained in hematoxylin for 10 minutes and immersed in 1% acid-alcohol. After placing cover slip cell layer down on a glass slide containing a drop of mounting medium, a microscope was used to observe the expression of SSTR2 in A2780/Taxol cells.

Effect of octreotide on A2780/Taxol cell proliferation

A2780/Taxol cells (5000) in the logarithmic phase were seeded in 96-well culture plates and cultured at 37°C under a 5% CO2 atmosphere for 24 hours. The cultured medium was removed when the cells adhered to the plate wall. The cells were then incubated in 100 µl of medium with octreotide at each concentration (0, 1.25, 2.5, 5, 10, and 20 nmol/ml). The blank control group used an equal volume of culture medium without the drugs. For each group, cells were cultured for setted time (24, 48, and 72 hours). Then treated with 10 µl of the Cell Counting Kit-8 (CCK-8) reagent for 3 hours. Absorbance (A) was measured on an enzyme-linked immunosorbent assay plate reader. The inhibition rate was calculated using the following formula:

Cell proliferation inhibition rate = (average of value A from the control group − the average of value A from the experimental group)/(average of value A from the control group − average of value A from blank controller) *100%. All experiments were repeated in triplicate and more than three wells were used for each treatment. A time-concentration curve was constructed using the average value of three tests.

Effect of octreotide on A2780/Taxol cell apoptosis

According to the CCK-8 results, A2780/Taxol cells were treated with octreotide at concentrations of 2.5, 5.0, and 10.0nmol/ml. An apoptosis test was carried out according to the instructions provided in the Annexin V-FITC/PI staining kit after 36 hours.

Effect of octreotide on SSTR2, MDR1, and VEGF mRNA expression in A2780/Taxol cells

Total RNA was extracted from the cells by Trizol. Dissolve the extracted RNA in diethylpyrocarbonate (DEPC) water. The absorption values at 260 and 280 nm were detected using an ultraviolet (UV) spectrophotometer. The RNA concentration was calculated using the following formula: RNA concentration = OD260 × dilution fold × 0.04 µg/µl. The OD260/280 value was in the range of 1.8 to 2.1, by UV spectroscopy. A 1 µg sample of total RNA was added to the reaction mixture, and the complementary deoxyribonucleic acid (cDNA) was synthesized according to the instructions provided in the reverse transcription polymerase chain reaction (RT-PCR) kit (Takara). Primers were designed and synthesized by the Houzai Company, as shown in [Table 1]. Real-time PCR was performed in a Light Cycler (Roche Applied Science) under the following conditions: Denaturation at 95°C for 2 minutes with an additional 10 seconds at 95°C, and a 40 seconds annealing at 60°C. Comparing the threshold method with the mathematical one, the amount of target gene was equal to 2-ΔΔct. Ct is the number of cycles of fluorescence required for it to reach the threshold:
Table 1: Primer sequences for the real-time PCR reaction

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ΔΔCt = (Ct objective gene – Ct reference gene) experimental group − (Ct objective gene – Ct reference gene) control group

Using this method, we were able to directly quantify the target gene relative to the reference gene (β-actin) and compare the common logarithm of the relative value of the target gene and control gene.

Effect of octreotide on SSTR2, MDR1, and VEGF protein expression in A2780/Taxol cells

Cells were lysed using modified radio-immunoprecipitation assay (RIPA) lysis buffer (1% NP-40, 0.25% deoxycholic acid, 50 mM Tris–HCl pH 7.4, 1 mM EDTA, 150 mM NaCl, 1 mM NaF, 1 μg/ml leupeptin, 1 mM PMSF, 1 mM sodium orthovanadate, 2 μg/ml pepstatin, 1 μg/ml aprotinin). Cell lysates were boiled with a loading buffer containing 3.3% glycerin, 1% SDS 20 mM TRIS pH 6.8, 23 mM β-mercaptoethanol freshly added, and 0.4 mg/ml bromophenol blue). Proteins were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) using precast 4–20% gradient gels and blotted to polyvinylidene difluoride (PDVF) with low autofluorescence. Immunodetection was carried out after blocking in 5% milk or gelatin in TTBS (20 mM Tris base, pH 7.5, 150mM NaCl, 0.05% Tween-20) and followed by incubation with diluted specific antibodies. Protein expression bands were scanned in gray scale (optical density (OD) value) scanning, using automatic image analysis system to quantitative analysis. Inhibition ratio of c-myc protein expression = (1 - c-myc OD value of experimental group/c-myc OD value of blank control group) 100%.

Statistical analysis

Statistical analysis was performed by statistical package of social sciences (SPSS) 16.0 software. Data are expressed as the means ± standard deviation (SD) and compared using the Student's t-test, analysis of variance (ANOVA) and correlation analysis. P <0.05 was considered statistically significant.


 > Results Top


Immunocytochamistry

[Figure 1] shows that SSTR2 had positive staining on the membrane of A2780/Taxol cells.
Figure 1: The expression of SSTR2 on A2780/Taxol cells Figure 1-1 Positive staining image of SSTR2 on A2780/Taxol cells. After immunocytochemistry, A2780/Taxol appear brown particles on cell surface, SSTR2 showed positive expression. Figure 1-2 Negative staining image with no primary antibody. Without a negative control antibody incubation, cells were stained blue-purple, and no brown particles on the surface

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Effect of octreotide on A2780/Taxol cell proliferation

Inhibitory effect began at the concentration of 1.25 nmol/ml. The increasing treatment enhanced the inhibitory effect. When the concentration >5 nmol/ml, the inhibition rate on A2780/Taxol cell proliferation was markedly increased. Significant differences were achieved between the control group and each of the octreotide treatment groups, and the difference also among the octreotide treatment groups at different concentrations (P < 0.05). According to the correlation analysis, the inhibition rate of cell proliferation was positively correlated with drug concentration (r = 0.977, P < 0.05) and positively correlated with treating time (r = 0.968, P < 0.05). The inhibition rate of cell proliferation was concentration-dependent and time-dependent [Table 2], [Figure 2].
Table 2: Inhibition rate of octreotide on A2780/Taxol cell proliferation at the indicated concentration and time

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Figure 2: Inhibition rate of octreotide on A2780/Taxol cell proliferation at the indicated concentration and time. Octreotide is displayed at different concentrations and time of A2780/Taxol cell proliferation inhibition rate of cell proliferation, thus octreotide is time and concentration-dependent

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Effect of octreotide on A2780/Taxol cell apoptosis

A2780/Taxol cell was treated with octreotide at concentrations 10.0, 5.0, 2.5 nmol/ml for 36 hours, the apoptosis rate was (26.14 ± 1.75%), (18.22 ± 2.012%), (11.77 ± 3.17%), respectively, and the apoptosis rate of control group was (6.98 ± 1.88%). Each concentration group was much more powerful than the control group (P < 0.05). The apoptosis rate gradually increased with the increased concentration, the difference was statistically significant (P < 0.05) [Figure 3].
Figure 3: Effects of octreotide on A2780/Taxolcell apoptosis (a) Control (b) octreotide 2.5 nmol/ml (c) octreotide 5.0 nmol/ml (d) octreotide 10.0 nmol/ml. Figure 3-1 is a flow diagram of different concentrations of octreotide after 36 hours, Figure 3-2 is a rate histogram of each group of data, showing that octreotide can promote A2780/Taxol apoptosis, and showed concentration-dependent manner

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SSTR2, MDR1, and VEGF mRNA expression in A2780/Taxol cells

[Figure 4] shows that SSTR2 mRNA was detected in each group, but there is no difference between the various concentrations (P > 0.05). Compared with the control group, both the expression of MDR1 and VEGF mRNA decreased in a dose-dependent manner following 48 hours of treatment of octreotide (P < 0.05).
Figure 4: Effect of octreotide on SSTR2, MDR1, and vascular endothelial growth factor (VEGF) messenger ribonucleic acid (mRNA) expression in A2780/Taxol cells. Figure 4 shows drug-related changes in gene expression in cells after 48 hours with different concentrations of octreotide effects, with increasing concentrations of octreotide, MDR1 expression and VEGF mRNA decline, in a concentration-dependent manner, whereas SSTR2 mRNA expression was not significantly increase or decrease trend

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SSTR2, MDR1, and VEGF protein expression in A2780/Taxol cells

The results of western blot shows that compared with the control group, both the expression of SSTR2, MDR1, and VEGF protein decreased in a dose-dependent manner following 48 hours of treatment of octreotide (P < 0.05) [Figure 5] and [Table 3].
Figure 5: Effect of octreotide on SSTR2, MDR1, and vascular endothelial growth factor (VEGF) protein expression in A2780/Taxol cells. Figure 5 shows the impact on the expression of the relevant A2780/Taxol-resistant cells after 48 hours of different concentrations of octreotide, with increasing concentrations of octreotide, SSTR2, MDR1, and VEGF protein expression decreased in a dose-dependent manner

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Table 3: Effect of octreotide on SSTR2, MDR1 and VEGF protien expression in A2780/Taxol cells

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 > Discussion Top


Paclitaxel combined with platinum remains the first-line chemotherapy in the treatment of ovarian cancer. However, due to resistance, it often fails to cure patients. Therefore, the reversal of paclitaxel resistance in ovarian cancer and increased sensitivity to paclitaxel-based chemotherapy drugs are crucial issues. It is important to explore new types of drugs that reverse paclitaxel resistance and enhance sensitivity to paclitaxel.

SST is located in most human organs and tissues and has a variety of functions, including the inhibition of hormone secretion, regulation of neural transmission, and cell proliferation. The SSTA not only inhibits the proliferation of neuroendocrine tumors in vitro, but also inhibits solid tumor growth in vivo.[7],[8] Octreotide, the most widely used SSTA in clinical applications was found to exhibit the highest binding affinity to SSTR2 and subsequently inhibits the activity of tyrosine phosphatase and the proliferation of SSTR2-expressing cells.[10],[11] Our earlier research has detected the expression of SSTR2 on the cell surface of SKOV3/DDP by RT-qPCR and has shown that octreotide could inhibit ovarian cancer proliferation and promote apoptosis, via the cell surface SSTR2, and reverse cisplatin resistance through inhibition of MRP2, EGFR, and even GST-π expressions.[12],[13] These results provide the possibility for the clinical use of SSTA in the treatment of ovarian cancer.

However, the function of octreotide in the enhancement of paclitaxel sensitivity in resistant ovarian cancer cells remains unclear. In this study, we evaluated the effects of octreotide on A2780/Taxol ovarian cancer cells in vitro, and to explore its potential molecular mechanism.

In this study, we proved that A2780/Taxol cells expressed SSTR2 by immunocytochemistry. So the results suggested that octreotide could effectively inhibit the proliferation of paclitaxel-resistant ovarian cancer A2780/Taxol cells in a dose-dependent manner and promoted the growth of apoptosis. Octreotide was cytotoxic to paclitaxel-resistant ovarian cancer cells in vitro.

Our previous study has shown that paclitaxel combined with octreotide could markedly inhibit the proliferation and promote apoptosis of cisplatin-resistant ovarian cancer cells, and the combination of the two single drugs has significant synergistic action. Furthermore, the researches of synthesized paclitaxel–octreotide conjugate and its effect on lung cancer cells have shown its cytotocity in vitro and in vivo.[14],[15],[16] The design for synthesis octreotide-conjugated taxol was based on the properties of SSTR endocytosis when octreotide binds to SSTR. Octreotide-conjugated taxol internalization into the cytosol of SSTR-expressing tumor cells could decrease the cytotoxicity of taxol in non-SSTR-expressing cells.[14] Previous studies have shown that the SSTR is expressed in ovarian cancer.[17],[18] Our earlier research has detected the expression of SSTR2 on the cell surface of SKOV3/DDP and has shown that octreotide could inhibit ovarian cancer's proliferation and promote its apoptosis, via the cell surface SSTR2, and reverse cisplatin resistance through inhibition of MRP2, EGFR, and even GST-π expressions.[12],[13] It suggests that SST and SSTA may be potential targets for ovarian cancer therapy.

In this study, the data suggested that octreotide inhibited A2780/Taxol cell proliferation, promoted cell apoptosis, and reversed chemotherapy resistance. However, the detailed mechanism is not clear yet. We investigated the expression of the resistance-related MDR1 and VEGF genes using qRT-PCR assays. Western blotting was used to investigate the expressions of SSTR2, MDR1, and VEGF proteins in A2780/Taxol cells.

The result of qRT-PCR suggests that octreotide does not alter the SSTR2 mRNA expression level, which is not consistent with a previous study.[11] These contrary results may be due to the different cell characteristics, expression of the receptor and their subtypes, and a high octreotide treatment concentration. Furthermore, mRNA is not reliable as an index to reflect the status of the receptor. So, we have detected the cell membrane localized receptor protein of SSTR2 by western blotting and the result suggests that octreotide could decrease the expressions of SSTR2 protein in a dose-dependent manner. Octreotide may take effect through decreasing SSTR2 expressions.

MDR1 was found to decrease the intracellular paclitaxel concentration by encoding cell surface transporter protein p-gp, resulting in reduced or loss of drug function and induced resistance in ovarian cancer cells.[19],[20],[21] This study demonstrated the decreasing of MDR1 expression in A2780/Taxol cells following the treatment of the octreotide both in gene and protein levels, suggesting that MDR1 may be involved in octreotide-mediated inhibition of cell proliferation and reversal of paclitaxel resistance.

VEGFA, commonly known as VEGF) is a key proangiogenic growth factor that plays a crucial role in tumor angiogenesis.[22] Akiyama K observed that VEGF secreted from tumors up-regulated MDR1 through the activation of VEGFR2 and Akt. MDR1 up-regulation, via the VEGF-VEGFR pathway in the tumor micro-environment, is one of the mechanisms of drug resistance acquired by tumor endothelial cells.[11] This study demonstrated the decreasing of VEGF expression of both gene and protein in A2780/Taxol cells following the treatment of the octreotide, suggesting that octreotide may take effects through decreasing VEGF expression.

In conclusion, this study demonstrates the effects of octreotide on A2780/Taxol cells and discusses the possible mechanism mediated by SSTR2, MDR1, and VEGF. This finding provides a new target for ovarian cancer therapy. However, the mechanism of the metabolism and transport mechanism from extracellular to intracellular remains unclear, which need to be approved in the following experiments. The significance of these changes requires further in vivo studies for verification.


 > Acknowledgments Top


This work was supported by Youth fund projects of Jiangsu Province Health Department (Q201305), Science and Technology Project of Nanjing City (201201054), Science and Technology Project of Nanjing City (200901089) and Southeast University Technology Fund (KJ2010493).

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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