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drug resistant AND tumor

Ganesan Muthusamy, Srithar Gunaseelan, Nagarajan Rajendra Prasad
In this study, the modulatory effect of ferulic acid on P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) was examined in KB ChR 8-5 resistant cells and drug-resistant tumor xenografts. We observed that ferulic acid enhanced the cytotoxicity of doxorubicin and vincristine in the P-gp overexpressing KB ChR 8-5 cells. Further, ferulic acid enhances the doxorubicin induced γH2AX foci formation and synergistically augmented doxorubicin-induced apoptotic signaling in the drug-resistant cells. It has also been noticed that NF-κB nuclear translocation was suppressed by ferulic acid and that this response might be associated with the modulation of phosphatidyinositol 3-kinase (PI3K)/Akt/signaling pathway...
October 12, 2018: Journal of Nutritional Biochemistry
Nasser Hashemi Goradel, Masoud Najafi, Eniseh Salehi, Bagher Farhood, Keywan Mortezaee
Cyclooxygenase-2 (COX-2) is frequently expressed in many types of cancers exerting a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and cancer cell resistance to chemo- and radiotherapy. COX-2 is released by cancer-associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the tumor microenvironment (TME). COX-2 induces cancer stem cell (CSC)-like activity, and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, invasion, and metastasis of cancer cells...
October 20, 2018: Journal of Cellular Physiology
Beaulah Mary Robert, Muralidharan Dakshinamoorthy, Brindha Ganapathyagraharam Ramamoorthy, Muthu Dhandapani, Radhiga Thangaiyan, Ganesan Muthusamy, R Madhavan Nirmal, Nagarajan Rajendra Prasad
Oral Squamous Cell Carcinoma (OSCC) patients respond poorly to chemotherapy. We analyzed the expression of 11 drug response-related genes in 31 OSCC biopsies, collected prior to any treatment, using custom-designed PCR array. Further, we investigated the drug response pattern of selected anticancer drugs by BH3 (Bcl2 Homology-3) profiling in the primary cells isolated from OSCC tissues. Then, we correlated the results of drug-response gene expression pattern with apoptotic priming to predict tumor response to chemotherapy...
October 19, 2018: Scientific Reports
Yuanyuan Yan, Fangxiao Liu, Li Han, Lin Zhao, Jianjun Chen, Olufunmilayo I Olopade, Miao He, Minjie Wei
BACKGROUND: Hypoxic tumor microenvironment and maintenance of stemness contribute to drug resistance in breast cancer. However, whether Hypoxia-inducible factor-2α (HIF-2α) in hypoxic tumor microenvironment mediates conversion to a stem cell phenotype and chemoresistance of breast tumors has not been elucidated. METHODS: The mRNA and protein expressions of HIF-1α, HIF-2α, Wnt and Notch pathway were determined using qRT-PCR and western blot. Cell viability and renew ability were assessed by MTT, Flow cytometric analysis and soft agar colony formation...
October 19, 2018: Journal of Experimental & Clinical Cancer Research: CR
Vania Vidimar, Cynthia Licona, Ricardo Cerón Camacho, Eric Guerin, Pierre Coliat, Aina Venkatasamy, Moussa Ali, Dominique Guenot, Ronan Le Lagadec, Alain C Jung, Jean-Noel Freund, Michel Pfeffer, Georg Mellitzer, Gianni Sava, Christian Gaiddon
Targeting specific tumor metabolic needs represents an actively investigated therapeutic strategy to bypass tumor resistance mechanisms. In this study, we describe an original approach to impact the cancer metabolism by exploiting the redox properties of a ruthenium organometallic compound. This organometallic complex induced p53-independent cytotoxicity and reduced size and vascularization of patients-derived tumor explants that are resistant to platinum drugs. At the molecular level, the ruthenium complex altered redox enzyme activities and the intracellular redox state by increasing the NAD+/NADH ratio and ROS levels...
October 16, 2018: Cancer Letters
Laurens E Franssen, Inger S Nijhof, Chad C Bjorklund, Hsiling Chiu, Ruud Doorn, Jeroen van Velzen, Maarten Emmelot, Berris van Kessel, Mark-David Levin, Gerard M J Bos, Annemiek Broijl, Saskia K Klein, Harry R Koene, Andries C Bloem, Aart Beeker, Laura M Faber, Ellen van der Spek, Reinier Raymakers, Pieter Sonneveld, Sonja Zweegman, Henk M Lokhorst, Anjan Thakurta, Xiaozhong Qian, Tuna Mutis, Niels W C J van de Donk
We recently showed that the outcome of multiple myeloma (MM) patients treated in the REPEAT study (evaluation of lenalidomide combined with low-dose cyclophosphamide and prednisone (REP) in lenalidomide-refractory MM) was markedly better than what has been described with cyclophosphamide-prednisone alone. The outcome with REP was not associated with plasma cell Cereblon expression levels, suggesting that the effect of REP treatment may involve mechanisms independent of plasma cell Cereblon-mediated direct anti-tumor activity...
September 21, 2018: Oncotarget
Enyuan Shang, Yiru Zhang, Chang Shu, Chiaki Tsuge Ishida, Elena Bianchetti, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin
XPO1 has recently emerged as a viable treatment target for solid malignancies, including glioblastoma (GBM), the most common primary malignant brain tumor in adults. However, given that tumors become commonly resistant to single treatments, the identification of combination therapies is critical. Therefore, we tested the hypothesis that inhibition of anti-apoptotic Bcl-2 family members and XPO1 are synthetically lethal. To this purpose, two clinically validated drug compounds, the BH3-mimetic, ABT263, and the XPO1 inhibitor, Selinexor, were used in preclinical GBM model systems...
October 18, 2018: Scientific Reports
Yongchun Zhou, Yuhui Ma, Hutao Shi, Yaxi Du, Yunchao Huang
To explore the effect of epidermal growth factor receptor (EGFR) T790M mutation status on non-small cell lung cancer (NSCLC) in Yunnan province of southwestern China. First, this study used the super amplification refractory mutation system (Super ARMS) polymerase chain reaction (PCR) and Droplet Digital PCR (dd PCR) to evaluate the T790M gene mutation, in plasmatic ctDNA samples from 212 cases of NSCLC. The association between T790M mutations and clinical parameters were further explored. Next, to investigate the mechanism of drug resistance that resulted from T790M mutation, subgroup analyses according to duration of medicine (EGFR-TKIs) were carried out...
October 18, 2018: Scientific Reports
Guocan Yu, Shan Yu, Manik Lal Saha, Jiong Zhou, Timothy R Cook, Bryant C Yung, Jin Chen, Zhengwei Mao, Fuwu Zhang, Zijian Zhou, Yijing Liu, Li Shao, Sheng Wang, Changyou Gao, Feihe Huang, Peter J Stang, Xiaoyuan Chen
Photodynamic therapy is an effective alternative to traditional treatments due to its minimally invasive nature, negligible systemic toxicity, fewer side effects, and avoidance of drug resistance. However, it is still challenging to design photosensitizers with high singlet oxygen (1 O2 ) quantum yields (QY) due to severe aggregation of the hydrophobic photosensitizers. Herein, we developed a discrete organoplatinum(II) metallacage using therapeutic cis-(PEt3 )2 Pt(OTf)2 as the building block to improve the 1 O2 QY, thus achieving synergistic anticancer efficacy...
October 18, 2018: Nature Communications
Hangsak Huy, Tae-Don Kim, Won Sam Kim, Dong Oh Kim, Jae-Eun Byun, Mi Jeong Kim, Young-Jun Park, Suk Ran Yoon, Ji-Yoon Noh, Jungwoon Lee, Kyoo-Hyung Lee, Inpyo Choi, Haiyoung Jung
Overcoming drug resistance is one of key issues in treating refractory acute myeloid leukemia (AML). The Toll-like receptor 4 (TLR4) signaling pathway is involved in many aspects of biological functions of AML cells, including the regulation of pro-inflammatory cytokine products, myeloid differentiation, and survival of AML cells. Thus, targeting TLR4 of AML patients for therapeutic purposes should be carefully addressed. In this regard, we investigated the possible role of TLR4 as a regulatory factor against fludarabine (FA) cytotoxicity activity...
October 15, 2018: Biochemical and Biophysical Research Communications
Rakesh K Pathak, Uttara Basu, Anis Ahmad, Shrita Sarkar, Anil Kumar, Bapurao Surnar, Saba Ansari, Katarzyna Wilczek, Michael E Ivan, Brian Marples, Nagesh Kolishetti, Shanta Dhar
Multimodal therapies are used to treat advanced cancers including castration-resistant prostate cancer to manage the biological characteristics of the tumors like inflammation, bone metastases, and participation of metabolically altered cancer stem cells (CSCs) that have integral roles in disease dissemination and progression. We developed a multifunctional polymer-based self-assembled technology to deliver a predefined stoichiometric combination of a chemotherapy and an anti-inflammatory agent in a stimuli responsive manner, to complement and improve the currently established treatment methods of prostate cancer...
September 5, 2018: Biomaterials
Yiming Bi, Han Li, Dazhuang Yi, Yuxue Sun, Yang Bai, Sheng Zhong, Yang Song, Gang Zhao, Yong Chen
Glioblastoma multiforme (GBM) is the most commonly encountered subtype of deadly brain cancer in human adults. It has a high recurrence rate and shows aggressive proliferation. The novel cytotoxic agent temozolomide (TMZ) is now frequently applied as the first-line chemotherapeutic treatment for GBM; however, a considerable number of patients treated with TMZ turn out to be refractory to this drug. Hence, a more effective therapeutic approach is urgently required to overcome this critical issue. Accumulating evidence has shown that both AMPK and AKT are activated by TMZ, while only AMPK contributes to apoptosis via mammalian target of rapamycin (mTOR) inhibition...
October 17, 2018: Molecular Pharmaceutics
Jeffrey R Gehlhausen, Eric Hawley, Benjamin Mark Wahle, Yongzheng He, Donna Edwards, Steven D Rhodes, Jacquelyn D Lajiness, Karl Staser, Shi Chen, Xianlin Yang, Jin Yuan, Xiaohong Li, Li Jiang, Abbi Smith, Waylan Bessler, George Sandusky, Anat Stemmer-Rachamimov, Timothy J Stuhlmiller, Steven P Angus, Gary L Johnson, Grzegorz Nalepa, Charles W Yates, D Wade Clapp, Su-Jung Park
Schwannomas are common, highly morbid, and medically untreatable tumors that can arise in patients with germline as well as somatic mutations in NF2. These mutations most commonly result in the loss of function of the NF2 encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells. Here, we identify NF-κB-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis...
October 17, 2018: Human Molecular Genetics
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
Jiacui Zhang, Keping Jiao, Jing Liu, Yu Xia
The nuclear factor, erythroid 2 like 2 (Nrf2)/antioxidant response element (ARE) pathway has an important role in the drug resistance of adenocarcinoma, and may act via different mechanisms, including the mitogen-activated protein kinase (MAPK) pathway. However, it has remained elusive whether metformin affects Nrf2 and regulates Nrf2/ARE in adenocarcinoma. In the present study, reverse-transcription quantitative polymerase chain reaction, cell transfection, western blot analysis, a Cell Counting kit-8 assay and apoptosis detection were used to investigate the above in the A549 cell line and cisplatin-resistant A549 cells (A549/DDP)...
November 2018: Oncology Letters
Hee Yeon Kim, Dong Keon Kim, Seung-Hyun Bae, HyeRan Gwak, Ji Hoon Jeon, Jong Kwang Kim, Byung Il Lee, Hye Jin You, Dong Hoon Shin, Young-Ho Kim, Soo Youl Kim, Sung-Sik Han, Jin-Kyoung Shim, Ji-Hyun Lee, Seok-Gu Kang, Hyonchol Jang
Glioblastoma is a highly malignant tumor that easily acquires resistance to treatment. The stem-cell-like character (stemness) has been thought to be closely associated with the treatment resistance of glioblastoma cells. In this study, we determined that farnesyl diphosphate synthase (FDPS), a key enzyme in isoprenoid biosynthesis, plays an important role in maintaining glioblastoma stemness. A comparison of the mRNA expression in patient-derived glioblastoma sphere cells, which maintain stemness, and their differentiated counterparts, which lose stemness, via RNA sequencing showed that most of the altered genes were networked in the cholesterol biosynthesis pathway...
October 17, 2018: Experimental & Molecular Medicine
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
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