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Cancer drug resistence

Carla Serri, Vincenzo Quagliariello, Rosario Vincenzo Iaffaioli, Sabato Fusco, Gerardo Botti, Laura Mayol, Marco Biondi
Combination chemotherapy by means of two or more drugs is prone to suppressing or discouraging the inception of multidrug resistance, exploiting the fact that diverse drugs act in different points of the cellular cycle of amplifying tumor cells. For example, the combination of gemcitabine (GMC) with quercetin (QCT) showed a synergistic effect in inhibiting the migration of pancreatic cancer cells. Consequently, herein GMC and QCT have been loaded within biodegradable nanoparticles (NPs) based on poly(lactic-co-glycolic acid), externally decorated with hyaluronic acid (HA; viz...
October 18, 2018: Journal of Cellular Physiology
Arjanneke F van de Merbel, Geertje van der Horst, Maaike H van der Mark, Janneke I M van Uhm, Erik J van Gennep, Peter Kloen, Lijkele Beimers, Rob C M Pelger, Gabri van der Pluijm
Urological malignancies, including prostate and bladder carcinoma, represent a major clinical problem due to the frequent occurrence of therapy resistance and the formation of incurable distant metastases. As a result, there is an urgent need for versatile and predictive disease models for the assessment of the individualized drug response in urological malignancies. Compound testing on ex vivo cultured patient-derived tumor tissues could represent a promising approach. In this study, we have optimized an ex vivo culture system of explanted human prostate and bladder tumors derived from clinical specimens and human cancer cell lines xenografted in mice...
2018: Frontiers in Oncology
Shogo Okazaki, Subaru Shintani, Yuki Hirata, Kentaro Suina, Takashi Semba, Juntaro Yamasaki, Kiyoko Umene, Miyuki Ishikawa, Hideyuki Saya, Osamu Nagano
The cystine-glutamate antiporter subunit xCT suppresses iron-dependent oxidative cell death (ferroptosis) and is therefore a promising target for cancer treatment. Given that cancer cells often show resistance to xCT inhibition resulting in glutathione (GSH) deficiency, however, we here performed a synthetic lethal screen of a drug library to identify agents that sensitize the GSH deficiency-resistant cancer cells to the xCT inhibitor sulfasalazine. This screen identified the oral anesthetic dyclonine which has been recently reported to act as a covalent inhibitor for aldehyde dehydrogenases (ALDHs)...
September 18, 2018: Oncotarget
Chin-Fu Chen, Chi-Cheng Lu, Jo-Hua Chiang, Hong-Yi Chiu, Jai-Sing Yang, Chao-Ying Lee, Tzong-Der Way, Hao-Jen Huang
Cetuximab, an epidermal growth factor receptor (EGFR)-targeting monoclonal antibody (mAb), is a novel targeted therapy for the treatment of patients with oral cancer. Cetuximab can be used in combination with chemotherapeutic agents to prolong the overall survival rates of patients with oral cancer. Curcumin is a traditional Chinese medicine, and it has been demonstrated to have growth-inhibiting effects on oral cancer cells. However, information regarding the combination of cetuximab and curcumin in drug-resistant oral cancer cells is lacking, and its underlying mechanism remains unclear...
November 2018: Oncology Letters
Tetsuya Minegaki, Ai Suzuki, Misato Mori, Shiori Tsuji, Satoshi Yamamoto, Airi Watanabe, Tomoyo Tsuzuki, Takaki Tsunoda, Asuka Yamamoto, Masayuki Tsujimoto, Kohshi Nishiguchi
Resistance to 5-fluorouracil (5-FU) is a serious problem in cancer therapy and overcoming it is required in order to improve the efficacy of cancer chemotherapy. Histone deacetylase (HDAC) inhibitors are used in cancer treatments and, recently, it has been reported that HDAC inhibitors can overcome resistance to various anti-cancer drugs in vitro . In the present study, a 5-FU-resistant breast cancer cell line was established, and the effects of HDAC inhibitors in these cells were examined. The 5-FU-resistant cell line MDA-MB-468 (MDA468/FU) was established by continuous exposure of the parental cells to 5-FU...
November 2018: Oncology Letters
Bo Cai, Limin Ma, Shaojun Nong, You Wu, Xin Guo, Jinxian Pu
Human bladder cancer is one of the most aggressive tumours known and has shown resistance to traditional chemotherapy, which depends heavily on DNA-damaging drugs. β-elemene is one of the least cytotoxic antitumor agents that are extracted from Curcuma aromatica salisb and it exhibits antitumor effects in many carcinomas. β-elemene has attracted the attention of clinicians and scientists worldwide due to its few side effects and limited effect on the bone marrow. However, the antitumor mechanism of β-elemene remains largely unstudied...
November 2018: Oncology Letters
Neng Wang, Bowen Yang, Xiaotong Zhang, Shengqi Wang, Yifeng Zheng, Xiong Li, Shan Liu, Hao Pan, Yingwei Li, Zhujuan Huang, Fengxue Zhang, Zhiyu Wang
Chinese formulas have been paid increasing attention in cancer multidisciplinary therapy due to their multi-targets and multi-substances property. Here, we aim to investigate the anti-breast cancer and chemosensitizing function of Ai Du Qing (ADQ) formula made up of Hedyotis diffusa , Curcuma zedoaria (Christm.) Rosc. , Astragalus membranaceus (Fisch.) Bunge , and Glycyrrhiza uralensis Fisch . Our findings revealed that ADQ significantly inhibited cell proliferation in both parental and chemo-resistant breast cancer cells, but with little cytotoxcity effects on the normal cells...
2018: Frontiers in Pharmacology
Gilar Gorji-Bahri, Atieh Hashemi, Hamid Reza Moghimi
Exosomes play a critical role in intercellular communication between cancer cells and their environments. These secreted nanovesicles can transfer different cargos such as mRNAs, proteins and microRNA (miRNA) to recipient cells. Exosomal miRNAs (exomiRs) derived from tumor cells have emerged as key players in cancer promotion via impairment of the immune system response, tumor growth, metastasis, angiogenesis, and chemotherapeutic drug resistance. Moreover, since dysregulation of miRNA expression in tumor cells can be reflected by distinct profiles of exomiRs extracted from the bodily fluids of cancer patients, they can be considered as non-invasive diagnostic, prognostic and predictive biomarkers...
October 17, 2018: Current Gene Therapy
Yoon Jin Cha, Ja Seung Koo
Adipocytes, which represent a substantial part of the tumor microenvironment in breast cancer, secrete several adipokines that affect tumorigenesis, cancer progression, metastasis and treatment resistance via multiple signaling pathways. Areas covered: In this review, we focus on the role of leptin, adiponectin, autotaxin and interleukin-6 in breast cancer initiation, progression, metastasis and drug response. Furthermore, we investigated adipokines as potential targets of breast cancer-specific drugs. Expert opinion: Adipokines and adipokine receptors are deregulated in breast cancer...
October 17, 2018: Expert Opinion on Therapeutic Targets
Susana Simões-Sousa, Samantha Littler, Sarah L Thompson, Paul Minshall, Helen Whalley, Bjorn Bakker, Klaudyna Belkot, Daniela Moralli, Daniel Bronder, Anthony Tighe, Diana C J Spierings, Nourdine Bah, Joshua Graham, Louisa Nelson, Catherine M Green, Floris Foijer, Paul A Townsend, Stephen S Taylor
Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically, however, karyotype heterogeneity drives tumor evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones...
October 16, 2018: Cell Reports
A Ziemys, K Yokoi, M Kai, Y T Liu, M Kojic, V Simic, M Milosevic, A Holder, M Ferrari
Metastatic disease is a major cause of mortality in cancer patients. While many drug delivery strategies for anticancer therapeutics have been developed in preclinical studies of primary tumors, the drug delivery properties of metastatic tumors have not been sufficiently investigated. Therapeutic efficacy hinges on efficient drug permeation into the tumor microenvironment, which is known to be heterogeneous thus potentially making drug permeation heterogeneous, also. In this study, we have identified that 4 T1 liver metastases, treated with pegylated liposomal doxorubicin, have unfavorable and heterogeneous transport of doxorubicin...
October 14, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Seyyed Mojtaba Mousavi, Seyyed Alireza Hashemi, Younes Ghasemi, Amir Atapour, Ali Mohammad Amani, Amir Savar Dashtaki, Aziz Babapoor, Omid Arjmand
Development of biologically inspired green synthesis of silver nanoparticles has attracted considerable worldwide attention in matter of medical science and disease treatment. Herein, the green synthesis of silver nanomaterials using organic green sources has been evaluated and discussed. These kinds of materials are widely used for treatment of antibiotic-resistant bacteria, cancer and etc due to their elegant properties compared with other chemical ways and drugs. Moreover, the outcome of green-based approaches were compared with chemical procedures and obtained data were examined via various analyses including UV-visible spectroscopy, scanning electron microscope (SEM), energy dispersive X-ray spectroscopy (EDX), transmission electron microscope (TEM), atomic force microscopy (AFM) and Fourier transforms infrared spectroscopy (FT-IR)...
October 17, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Weihong Guo, Lizhi Deng, Zhaoyu Chen, Zhian Chen, Jiang Yu, Hao Liu, Tuanjie Li, Tian Lin, Hao Chen, Mingli Zhao, Liming Zhang, Guoxin Li, Yanfeng Hu
AIM: Our previous research has introduced sericin micelles to reverse drug resistance. However, these micelles could not selectively bind to gastric cancer (GC) cells. We developed vitamin B12 (VB12) conjugated sericin micelles for targeted GC therapy. MATERIALS & METHODS: We used VB12, sericin, synthetic poly(γ-benzyl-L-glutamate) (PBLG) and paclitaxel (PTX) to develop VB12-conjugated and PTX-loaded micelles (VB12-sericin-PBLG-PTX). Then we explored their physicochemical properties, cellular uptake and antitumor mechanism...
October 17, 2018: Nanomedicine
Nurbubu T Moldogazieva, Sergey V Lutsenko, Alexander A Terentiev
Cancer is a complex disorder extremely dependent on its microenvironment and highly regulated by multiple intracellular and extracellular stimuli. Studies show that reactive oxygen and nitrogen species (RONS) play key roles in cancer initiation and progression. Accumulation of RONS caused by imbalance between RONS generation and activity of antioxidant system (AOS) has been observed in many cancer types. This leads to alterations in gene expression levels, signal transduction pathways, and protein quality control machinery, that is, processes that regulate cancer cell proliferation, migration, invasion, and apoptosis...
October 16, 2018: Cancer Research
Caterina Bartolacci, Cristina Andreani, Claudia Curcio, Sergio Occhipinti, Luca Massaccesi, Mirella Giovarelli, Roberta Galeazzi, Manuela Iezzi, Martina Tilio, Valentina Gambini, Junbiao Wang, Cristina Marchini, Augusto Amici
Δ16HER2 is a splice variant of HER2 and defined as the transforming isoform in HER2-positive breast cancer. It has been shown that Δ16HER2 promotes breast cancer aggressiveness and drug resistance. In the present work, we used in silico modelling to identify structural differences between Δ16HER2 and the wild-type HER2 proteins. We then developed DNA vaccines specifically against the Δ16HER2 isoform and showed that these immunotherapies hampered carcinogenesis in a breast cancer transplantable model. However, the vaccines failed to elicit immune protection in Δ16HER2 transgenic mice because of tolerogenic mechanisms towards the human HER2 self-antigen, a scenario commonly seen in HER2+ patients...
October 16, 2018: Cancer Immunology Research
Benjamin M Larimer, Emily G Bloch, Sarah Nesti, Emily E Austin, Eric Wehrenberg-Klee, Genevieve Boland, Umar Mahmood
PURPOSE: The lack of a timely and reliable measure of response to cancer immunotherapy has confounded understanding of mechanisms of resistance and subsequent therapeutic advancement. We hypothesized that PET imaging of granzyme B using a targeted peptide, GZP, could be utilized for early response assessment across many checkpoint inhibitor combinations, and that GZP uptake could be compared between therapeutic regimens and dosing schedules as an early biomarker of relative efficacy. EXPERIMENTAL DESIGN: Two models, MC38 and CT26, were treated with a series of checkpoint inhibitors...
October 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sandra Misale, Jackson P Fatherree, Eliane Cortez, Chendi Li, Samantha J Bilton, Daria Timonina, Dana Lee, Maria Gomez-Caraballo, Max Greenberg, Varuna Nangia, Patricia Greninger, Regina K Egan, Joseph D McClanaghan, Giovanna T Stein, Ellen Murchie, Patrick P Zarrinkar, Matthew R Janes, Lian-Sheng Li, Yi Liu, Aaron N Hata, Cyril H Benes
PURPOSE: KRAS mutant lung cancers have been recalcitrant to treatments including those targeting the MAPK pathway. Covalent inhibitors of KRAS p.G12C allele allow for direct and specific inhibition of mutant KRAS in cancer cells. However, as for other targeted therapies, the therapeutic potential of these inhibitors can be impaired by intrinsic resistance mechanisms. Therefore, combination strategies are likely needed to improve efficacy. EXPERIMENTAL DESIGN: To identify strategies to maximally leverage direct KRAS inhibition we defined the response of a panel of NSCLC models bearing the KRAS G12C activating mutation in vitro and in vivo...
October 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Yawei Shi, Yang Zhao, Yunjian Zhang, NiJiati AiErken, Nan Shao, Runyi Ye, Ying Lin, Shenming Wang
BACKGROUND: Although tamoxifen is a highly effective drug for treating estrogen receptor-positive (ER+ ) breast cancer, nearly all patients with metastasis with initially responsive tumors eventually relapse, and die from acquired drug resistance. Unfortunately, few molecular mediators of tamoxifen resistance have been described. Here, we describe AFF3 (AF4/FMR2 family member 3), which encodes a nuclear protein with transactivation potential that confers tamoxifen resistance and enables estrogen-independent growth...
October 16, 2018: Journal of Experimental & Clinical Cancer Research: CR
Yang Liu, Li Guo, Mire Zloh, Yujuan Zhang, Jinhu Huang, Liping Wang
Florfenicol (FFC) is a valuable synthetic fluorinated derivative of thiamphenicol widely used to treat infectious diseases in food animals. The aims of the study were to investigate whether FFC is a substrate for the breast cancer resistance protein (BCRP) and whether the transporter influences oral availability of FFC. In vitro transport assays using MDCK-chAbcg2 cells were conducted to assess chicken BCRP-mediated transport of FFC, while in vivo pharmacokinetic experiments with single or combined BCRP inhibitor gefitinib were employed to study the role of BCRP in oral FFC disposition...
October 15, 2018: International Journal of Molecular Sciences
Lavinia A Carabet, Nada Lallous, Eric Leblanc, Fuqiang Ban, Helene Morin, Sam Lawn, Fariba Ghaidi, Joseph Lee, Ian G Mills, Martin E Gleave, Paul S Rennie, Artem Cherkasov
While Myc is an essential regulator of growth in normal cells, it is also frequently associated with cancer progression, therapy-resistance and lethal outcomes in most human cancers. In prostate cancer (PCa), Myc transcription factors are implicated in the pathogenesis and progression of the full spectrum of PCa, from adenocarcinoma to advanced castration-resistant and neuroendocrine phenotypes. Though a high-value therapeutic target, clinically approved anti-Myc drugs have yet to be discovered. To elicit its oncogenic effects, Myc must form a heterodimer with its partner Max, which together bind DNA and activate transcription of a spectrum of target genes that promote cell growth, proliferation, metabolism, and apoptosis while blocking differentiation...
September 11, 2018: European Journal of Medicinal Chemistry
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