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Midkine as a potential diagnostic marker in epithelial ovarian cancer for cisplatin/paclitaxel combination clinical therapy.

ABSTRACT: The paclitaxel/cisplatin combination therapy commonly is used as the first-line treatment for advanced ovarian cancer patients. Midkine (MK), known as a novel tumor biomarker, has been elevated in the serum of patients with epithelial ovarian cancer (EOC). In this study, we aimed to detect the expression of MK in EOC tissues and evaluate clinical value of MK in diagnosis and therapy of EOC. We perform immunohistochemistry analysis to detect MK in EOC sample with postoperative platinum/paclitaxel combination therapy, we found that 71.4% (85 in 119 samples) of these samples were MK positive (> 10% of the cells were stained), and the expression of MK was significantly associated with disease histology (P = 0.038) as well as differentiation grade (P < 0.001). Moreover, MK positive samples show much more sensitive to cisplatin/paclitaxel combination therapy, compared with MK negative samples (P = 0.029). Those results indicated that MK expression might correlate with paclitaxel and/or cisplatin cytotoxicity in clinical therapy of EOC. Then, we evaluated the sensitivity to cisplatin and paclitaxel in 5 ovarian cancer cell lines (ES2, A2870, HO-8910, SKOV3 and SW626), and ES2, the highest MK expression among those cell lines, show the most sensitive to paclitaxel and cisplatin. Further, we confirmed this correlation between MK and paclitaxel and/or cisplatin cytotoxicity with the gain- and lost- of function. Finally, we demonstrated that MK enhanced the cytotoxicity of paclitaxel and/or cisplatin by accumulated cisplatin and paclitaxel through inhibited the expression of multidrug resistance-associated protein 3 (MRP3). In conclusion, MK could be an effective biomarker in diagnosis and therapy of EOC, especially for the drug selection at the time of initial diagnosis.

SUBMITTER: Wu X

PROVIDER: S-EPMC4396029 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Midkine as a potential diagnostic marker in epithelial ovarian cancer for cisplatin/paclitaxel combination clinical therapy.

Wu Xiaoqing X Zhi Xiaogai X Ji Minghua M Wang Qingling Q Li Yujuan Y Xie Jingyan J Zhao Shuli S

American journal of cancer research 20150115 2

The paclitaxel/cisplatin combination therapy commonly is used as the first-line treatment for advanced ovarian cancer patients. Midkine (MK), known as a novel tumor biomarker, has been elevated in the serum of patients with epithelial ovarian cancer (EOC). In this study, we aimed to detect the expression of MK in EOC tissues and evaluate clinical value of MK in diagnosis and therapy of EOC. We perform immunohistochemistry analysis to detect MK in EOC sample with postoperative platinum/paclitaxel ...[more]

PMID: 25973302

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Project description:Ovarian cancer is the most lethal type of gynecological cancer. Due to its high heterogeneity and complicated pathological mechanisms, the 5-year survival rate of patients with ovarian cancer is <40%. Tumor cytoreductive surgery and systemic chemotherapy of platinum combined with paclitaxel are currently considered the gold standard for the treatment of ovarian cancer, and chemotherapy resistance has become a key constraint in improving the cure rate of ovarian cancer. Therefore, it is important to identify novel treatment methods and strategies for ovarian cancer. Targeted drugs can not only be used in combination with chemotherapy, but also act as maintenance therapy to promote patient survival time. PARP inhibitor is a novel type of ovarian cancer treatment targeted drug, which can induce an anticancer effect by inhibiting DNA damage and repair of ovarian cancer cells. The present study investigated the different effects of olaparib, cisplatin and paclitaxel in several dosages by single use and combinations on the proliferation of different human ovarian cancer cell lines, in order to verify the synergistic effects of the combinations of the three anticancer agents in pairs. The proliferation inhibitory rate of the cell lines was determined using a Cell Counting Kit-8 assay, while the combination index (CI) value of the combination of three agents in pairs was analyzed using Compusyn software. The proliferation was observed using a crystal violet assay, and the apoptosis ratio was measured via flow cytometry. The results of the present study revealed that the combination of cisplatin with olaparib group had a higher inhibition effect than each single group and had a higher dose-reduction index of >1 than the other two combinations at all concentrations in A2780 and OVCAR-3 cell lines. The difference in proliferation inhibition and induced apoptosis rate of A2780 cell lines was significant in the combination of cisplatin with olaparib group and the control group (P<0.01) at 0.25x IC50. For the OVCAR-3 cell line, the difference was also significant between two groups (P<0.05). The CI values in the A2780 cell line revealed significant differences between the low-dose group (0.0625x, 0.125x and 0.25x IC50) and the high-dose group (0.5x, 1.0x and 2.0x IC50) for the group that received the combination of cisplatin with olaparib (P<0.05). The present study highlighted that the group receiving a combination of cisplatin with olaparib exhibited the most significant synergistic effects among the three combinations, particularly at low doses.

Project description:Ten human ovarian cancer cell lines were kindly provided as follows: an ovarian serous adenocarcinoma cell line, SKOV3 (Dr. N. Nagai, Hiroshima University, Hiroshima, Japan); KF28 and its TXL/CDDP-resistant variant (Dr. Y. Kikuchi, National Defense Medical College, Saitama, Japan); KF, SHIN3 and 5 ovarian clear cell adenocarcinoma cell lines, KK, TAYA, RMG-1, OVISE and OVTOKO (Dr. M. Suzuki, Jichi Medical School, Tochigi, Japan). All cell lines were cultured in RPMI 1640 medium (Life Technologies, Inc., Grand Island, NY) containing 10% heat-inactivated fetal bovine serum (FBS; BioWhittaker, Verviers, Belgium) in a humidified atmosphere of 5% CO2 and maintained in continuous exponential growth by passage every 3 days. Exponentially growing cultured cells were collected after two-washings with PBS. The cell pellets were immediately frozen in liquid nitrogen, and stored until use. Total RNA was extracted using QIAGEN RNeasy mini kit (QIAGEN, Inc., Valencia, CA). The quality of the RNA was checked using Agilent Technologies 2100 Bioanalyzer (Agilent, Palo Alto, CA). CodeLink Expression Bioarray System (Amersham Bioscience, Tokyo, Japan) was used according to the manufacturer’s protocol. Briefly, first-strand cDNA was generated from 1 microgram of total RNA of each cell line using reverse transcriptase and a T7 primer, and then second-strand cDNA was produced using DNA polymerase mix and RNase H. Complementary RNA (cRNA) was generated via an in vitro transcription reaction using T7 RNA polymerase and biotin-11-UTP (Perkin Elmer, Boston, MA), which was quantified by spectrometry and checked using Agilent Technologies 2100 Bioanalyzer (Agilent). Ten-microgram of cRNA was then fragmented and hybridized to a Uniset Human 20K I Bioarray containing 19,881 probes with positive and negative bacterial control probes. After hybridization, the arrays were rinsed and labeled with Streptavidin-Cy5, scanned using Agilent DNA Microarray Scanner (Agilent), then analyzed with CodeLink Expression Analysis Software ver.2.3. Expression levels were normalized to the median expression value of the whole array spots. Keywords: parallel sample

Project description:Background Metformin use is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models. The primary objective of this phase I study was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were to describe safety and pharmacokinetics. Methods In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175 mg/m2 every 3 weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3?+?3 escalation rule at three fixed dose levels: 500 mg three times daily (tds), 850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3 weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or???1 of 6 evaluable subjects experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) analyses were collected during treatment cycles 1 and 2. Results Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (n?=?5) or palliative (n?=?10) treatment were included. No DLTs were observed. Three patients discontinued study treatment during cycle 1 for other reasons than DLT. Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse events (AEs) occurred in ten patients, most common were leucopenia (n?=?4), thrombocytopenia (n?=?3) and increased GGT (n?=?3). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (?22%, p?=?0.013) and decreased the Pt clearance (?-28%, p?=?0.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1-4 mg/L). Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.

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Midkine as a potential diagnostic marker in epithelial ovarian cancer for cisplatin/paclitaxel combination clinical therapy.

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Midkine as a potential diagnostic marker in epithelial ovarian cancer for cisplatin/paclitaxel combination clinical therapy.

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