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ovarian cancer drug resistance

Zhenhua Li, Xin Tang, Yu Luo, Bangyu Chen, Congcong Zhou, Xiuqing Wu, Zhenping Tang, Xiaojie Qi, Guangchao Cao, Jianlei Hao, Zonghua Liu, Qingmin Wang, Zhinan Yin, Hengwen Yang
Ovarian cancer resistance to available medicines is a huge challenge in dire need of a solution, which makes its recurrence and mortality rate further exacerbated. A promising approach to overcome chemoresistance is drug screening from natural products. Here, we report that NK007, a (±)-tylophorine malate isolated from the Asclepiadaceae family, selectively inhibited the proliferation of A2780 and A2780 (Taxol) cells and migration of paclitaxel-sensitive and -resistant ovarian cancer cells. Interestingly, the decline of cell viability, including cell multiplication, clonality, and migration capacity was independent on cell apoptosis...
February 20, 2019: Journal of Cellular Physiology
Han Wang, Zihan Qiu, He Liu, Amarasooriya M D S Jayawardhana, Zhizhou Yue, Hala Daghlas, David J Bowers, Bansidhar Datta, Yao-Rong Zheng
A long-standing challenge in the treatment of ovarian cancer is drug resistance to standard platinum-based chemotherapy. Recently, increasing attention has been drawn to the use of self-assembled metal-organic complexes as novel therapeutics for cancer treatment. However, high hydrophobicity that is often associated with these structures lowers their solubility and hinders their clinical translation. In this article, we present a proof-of-concept study of using nanoprecipitation to formulate the hydrophobic metal-organic cages and facilitate their use in treating chemoresistant ovarian cancer...
2019: Frontiers in Chemistry
Koji Nakamura, Kenjiro Sawada, Mayuko Miyamoto, Yasuto Kinose, Akihiko Yoshimura, Kyoso Ishida, Masaki Kobayashi, Aasa Shimizu, Erika Nakatsuka, Kae Hashimoto, Seiji Mabuchi, Tadashi Kimura
Paclitaxel is a first-line drug for treating epithelial ovarian cancer (EOC). However, prognosis for patients with advanced stage cancer remains poor due to primary or acquired drug resistance. Therefore, overcoming chemoresistance is one of the greatest challenges in treating EOC. In this study, we identified microRNAs (miRNA) that regulate paclitaxel resistance and tested their potential utility as therapeutic targets. Paclitaxel-resistant cell lines were established using two EOC cell lines: SKVO3ip1 and HeyA8...
January 18, 2019: Oncotarget
Ya'nan Yang, Song Li, Yiting Sun, Di Zhang, Zeyi Zhao, Lian Liu
Purpose: Peritoneal metastasis is the most common pathway for the spread of ovarian cancer. Ovarian cancer cells in ascites prefer to aggregate into the more chemoresistant multicellular spheroids (MCSs), leading to treatment failure and disease recurrence. We previously established a suspension MCS model of ovarian cancer cells in vitro and found that the MCS cells acquired drug resistance to cisplatin. In the present study, we aimed to uncover the underlying mechanism of the platinum resistance of MCS and the potential targets to reverse the drug resistance...
2019: OncoTargets and Therapy
Xiaolan Zhu, Huiling Shen, Xinming Yin, Meiling Yang, Hong Wei, Qi Chen, Fan Feng, Yueqin Liu, Wenlin Xu, Yuefeng Li
BACKGROUND: How exosomal microRNAs (miRNAs) derived from macrophages contribute to the development of drug resistance in the context of the hypoxic tumor microenvironment in epithelial ovarian cancer (EOC) remains poorly understood. METHODS: The miRNA levels were detected by qRT-PCR. Protein levels of HIF-1α, CD163 and PTEN-PI3K/AKT pathway were assessed by Western blot (WB) and Immunohistochemistry (IHC). Exosomes were isolated, and then confirmed by Transmission electron microscopy (TEM), Nanoparticle Tracking Analysis (NTA) and WB...
February 15, 2019: Journal of Experimental & Clinical Cancer Research: CR
Shipeng Gong, Yongning Chen, Fanliang Meng, Yadi Zhang, Huan Wu, Chanyuan Li, Guangping Zhang
Currently, cisplatin (DDP) is the first-line chemotherapeutic agent used for treatment of ovarian cancer, but gradually acquired drug resistance minimizes its therapeutic outcomes. We aimed to identify crucial genes associated with DDP resistance in ovarian cancer and uncover potential mechanisms. Two sets of gene expression data were downloaded from Gene Expression Omnibus, and bioinformatics analysis was conducted. In our study, the differentially expressed genes between DDP-sensitive and DDP-resistant ovarian cancer were screened in GSE15709 and GSE51373 database, and chromosome condensation 2 regulator (RCC2) and nucleoporin 160 were identified as 2 genes that significantly up-regulated in DDP-resistant ovarian cancer cell lines compared with DDP-sensitive cell lines...
February 15, 2019: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Maria Bonello, Andrew Harvey Sims, Simon Peter Langdon
Ovarian cancer is the second most lethal gynecological cancer worldwide and while most patients respond to initial therapy, they often relapse with resistant disease. Human epidermal growth factor receptors (especially HER1/EGFR and HER2/ERBB2) are involved in disease progression; hence, strategies to inhibit their action could prove advantageous in ovarian cancer patients, especially in patients resistant to first line therapy. Monoclonal antibodies and tyrosine kinase inhibitors are two classes of drugs that act on these receptors...
November 2018: Cancer Biology & Medicine
Isabelle Matte, Perrine Garde-Granger, Paul Bessette, Alain Piché
About 20% of patients with high grade serous epithelial ovarian carcinoma (HGSOC) are intrinsically resistant to standard first-line platinum-based combination therapy. There is no marker yet available to identify these patients. In that context, all patients with HGSOC initially receive the same standard first-line platinum-based therapy, and those with intrinsically resistant diseases can only be identified retrospectively after they experienced early relapse to therapy. The aim of this study was to evaluate serum or ascites CA125 and ascites leptin in patients with intrinsic resistance and to compare them with those of sensitive patients...
2019: American Journal of Cancer Research
Rachael Mooney, Asma Abdul Majid, Jennifer Batalla-Covello, Diana Machado, Xueli Liu, Joanna Gonzaga, Revathiswari Tirughana, Mohamed Hammad, Maciej S Lesniak, David T Curiel, Karen S Aboody
Oncolytic virotherapy is a promising approach for treating recurrent and/or drug-resistant ovarian cancer. However, its successful application in the clinic has been hampered by rapid immune-mediated clearance or neutralization of the virus, which reduces viral access to tumor foci. To overcome this barrier, patient-derived mesenchymal stem cells have been used to deliver virus to tumors, but variability associated with autologous cell isolations prevents this approach from being broadly clinically applicable...
March 29, 2019: Molecular Therapy Oncolytics
Xiaoyan Hu, Yang Meng, Lian Xu, Lei Qiu, Mingtian Wei, Dan Su, Xu Qi, Ziqiang Wang, Shengyong Yang, Cong Liu, Junhong Han
CRL4, a well-defined E3 ligase, has been reported to be upregulated and is proposed to be a potential drug target in ovarian cancers. However, the biological functions of CRL4 and the underlying mechanism regulating cancer chemoresistance are still largely elusive. Here, we show that CRL4 is considerably increased in cisplatin-resistant ovarian cancer cells, and CRL4 knockdown with shRNAs is able to reverse cisplatin-resistance of ovarian cancer cells. Moreover, CRL4 knockdown markedly inhibits the expression of BIRC3, one of the inhibitors of apoptosis proteins (IAPs)...
February 4, 2019: Cell Death & Disease
Masahiro Yamamoto, Shuhei Suzuki, Keita Togashi, Tomomi Sanomachi, Shizuka Seino, Chifumi Kitanaka, Masashi Okada
BACKGROUND/AIM: AS602801, an anti-cancer stem cell (CSC) candidate drug, sensitizes ovarian CSCs to paclitaxel and carboplatin by reducing the expression of survivin, an anti-apoptotic protein. The aim of the study was to examine the effect of AS602801 on the expression of multi drug resistance protein 1 (MDR1). MATERIALS AND METHODS: Using two ovarian CSC lines, A2780 CSLC and TOV-21G CSLC, mechanisms other than survivin down-regulation were examined by comparing the effects of AS602801 and YM155, an inhibitor of survivin...
February 2019: Anticancer Research
Lu-Yao Guan, Yuan Lu
Ovarian cancer remains the most mortal gynecological cancer in the world. The standard treatment for ovarian cancer remains cytoreductive surgery followed by platinum-based chemotherapy. Although most patients are platinum-sensitive initially, the majority of them will develop platinum resistance after multiple relapses, and platinum-resistant patients have a low response to the second-line chemotherapy. Besides, ovarian cancer is considered to be a highly heterogeneous disease at the molecular level. Molecular targeted therapy is expected to be a more effective and less toxic therapeutic strategy for ovarian cancer...
November 2018: Discovery Medicine
Hye Joung Choi, Jin Hyung Heo, Ju Yeon Park, Ju Yeon Jeong, Hyeon Ju Cho, Kyung Soon Park, Se Hwa Kim, Yong Wha Moon, Jin Sung Kim, Hee Jung An
OBJECTIVE: Ovarian cancer is the leading cause of gynecologic-related mortality worldwide. Despite successful initial treatment, overall survival rates are very low because tumors develop resistance to chemotherapeutic drugs. The PI3K/mTOR pathway is a key signaling pathway involved in drug resistance of ovarian cancer cells. The aim of this study was to examine the effect of a newly developed PI3K/mTOR dual inhibitor, CMG002, on chemoresistant ovarian cancer cells. METHODS: We examined the effects of CMG002, and its synergistic effects when combined with paclitaxel or cisplatin, on cell viability, cell cycle arrest, and apoptosis of PTX-resistant SKpac17 or cisplatin-resistant A2780cis ovarian cancer cells in vitro...
January 25, 2019: Gynecologic Oncology
Claudia Iavarone, Ioannis K Zervantonakis, Laura M Selfors, Sangeetha Palakurthi, Joyce F Liu, Ronny Drapkin, Ursula A Matulonis, Dorothy Hallberg, Victor E Velculescu, Joel D Leverson, Deepak Sampath, Gordon B Mills, Joan S Brugge
Most patients with late stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient-derived xenograft (PDX) models...
January 24, 2019: Molecular Cancer Therapeutics
Delphine Naud-Martin, Corinne Landras-Guetta, Daniela Verga, Deepanjan Ghosh, Sylvain Achelle, Florence Mahuteau-Betzer, Sophie Bombard, Marie-Paule Teulade-Fichou
Guanine-rich DNA can form four-stranded structures called G-quadruplexes (G4s) that can regulate many biological processes. Metal complexes have shown high affinity and selectivity toward the quadruplex structure. Here, we report the comparison of a panel of platinum (II) complexes for quadruplex DNA selective recognition by exploring the aromatic core around terpyridine derivatives. Their affinity and selectivity towards G4 structures of various topologies have been evaluated by FRET-melting (Fluorescence Resonance Energy Transfert-melting) and Fluorescent Intercalator Displacement (FID) assays, the latter performed by using three different fluorescent probes (Thiazole Orange (TO), TO-PRO-3, and PhenDV)...
January 23, 2019: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Zhifa Cao, Qian Gao, Meixian Fu, Nan Ni, Yuting Pei, Wen-Bin Ou
Receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) serves a crucial role in brain development. ALK is located on the short arm of chromosome 2 (2p23) and exchange of chromosomal segments with other genes, including nucleophosmin ( NPM ), echinoderm microtubule-associated protein-like 4 ( EML4 ) and Trk -fused gene ( TFG ), readily occurs. Such chromosomal translocation results in the formation of chimeric X-ALK fusion oncoproteins, which possess potential oncogenic functions due to constitutive activation of ALK kinase...
February 2019: Oncology Letters
Jue Liu, Xiaobo Zhang, Yuliang Huang, Qunfeng Zhang, Jianbin Zhou, Xiaodi Zhang, Xiaoxu Wang
Cisplatin is a first-line chemotherapy drug that is commonly used in the treatment of epithelial ovarian cancer (EOC). However, insensitivity to cisplatin markedly influences the outcomes of chemotherapy. MicroRNAs (miRNAs/miRs) have been demonstrated to modulate drug resistance in a number of types of cancer. The aim of the present study was to investigate the key miRNAs involved in modulating drug resistance in ovarian cancer cells. miR-200b and miR-200c were identified to be frequently deregulated in ovarian cancer...
February 2019: Oncology Letters
Giovanna Damia, Massimo Broggini
Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. It is initially responsive to cisplatin and carboplatin, two DNA damaging agents used in first line therapy. However, almost invariably, patients relapse with a tumor resistant to subsequent treatment with platinum containing drugs. Several mechanisms associated with the development of acquired drug resistance have been reported. Here we focused our attention on DNA repair mechanisms, which are fundamental for recognition and removal of platinum adducts and hence for the ability of these drugs to exert their activity...
January 20, 2019: Cancers
George E Duran, Branimir I Sikic
In a previously published study, higher levels of spleen tyrosine kinase (Syk) were observed in recurrent post-chemotherapy ovarian cancers compared to primary tumors. Syk inhibition was found to stabilize microtubules and potentiate paclitaxel activity in cellular models of taxane-resistant ovarian cancers. We further studied the effects of Syk inhibition on paclitaxel activity in Syk(+) ovarian cancer cell models and in variants selected for taxane resistance. Syk inhibition was accomplished using RNAi and by exposure to the small molecule competitive inhibitor R406, the active metabolite of fostamatinib...
2019: PloS One
Yu Zhang, Liang Tao, Li-Xia Fan, Kun Huang, Hui-Min Luo, Hui Ge, Xiyan Wang, Qin Wang
Our previous study demonstrated that connexin 32 (Cx32) was upregulated and redistributed to the cytoplasm in A2780 human ovarian cancer cells with acquired resistance to cisplatin; this increased Cx32 feedback promoted cisplatin resistance. To further investigate the mechanism underlying Cx32‑mediated cisplatin resistance, alterations in drug transporters, the DNA repair system and the anti‑apoptotic signalling pathway were investigated by overexpressing or knocking down Cx32 in parental cells (A2780); cisplatin‑resistant human ovarian cancer cells (A2780/CDDP) were also acquired...
January 17, 2019: Molecular Medicine Reports
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