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Autophagy and chemotherapy resistance

Mihwa Kim, Ji-Yeon Jung, Seungho Choi, Hyunseung Lee, Liza D Morales, Jeong-Tae Koh, Sun Hun Kim, Yoo-Duk Choi, Chan Choi, Thomas J Slaga, Won Jae Kim, Dae Joon Kim
Recent progress in chemotherapy has significantly increased its efficacy, yet the development of chemoresistance remains a major drawback. In this study, we show that GFRA1/GFRα1 (GDNF family receptor alpha 1), contributes to cisplatin-induced chemoresistance by regulating autophagy in osteosarcoma. We demonstrate that cisplatin treatment induced GFRA1 expression in human osteosarcoma cells. Induction of GFRA1 expression reduced cisplatin-induced apoptotic cell death and it significantly increased osteosarcoma cell survival via autophagy...
October 18, 2016: Autophagy
Nargis Khan, Susanta Pahari, Aurobind Vidyarthi, Mohammad Aqdas, Javed N Agrewala
Tuberculosis (TB) is the leading cause of morbidity and mortality among all infectious diseases. Failure of Bacillus Calmette Guerin as a vaccine and serious side-effects and toxicity due to long-term TB drug regime are the major hurdles associated with TB control. The problem is further compounded by the emergence of drug-resistance strains of Mycobacterium tuberculosis (Mtb). Consequently, it demands a serious attempt to explore safer and superior treatment approaches. Recently, an improved understanding of host-pathogen interaction has opened up new avenues for immunotherapy for treating TB...
2016: Frontiers in Immunology
Fang Ren, Jacson Shen, Huirong Shi, Francis J Hornicek, Quancheng Kan, Zhenfeng Duan
Ovarian cancer remains the leading cause of gynecological cancer-related mortality despite the advances in surgical techniques and chemotherapy drugs over the past three decades. Multidrug resistance (MDR) to chemotherapy is the major cause of treatment failure. Previous research has focused mainly on strategies to reverse MDR by targeting the MDR1 gene encoded P-glycoprotein (Pgp) with small molecular compound inhibitors. However, prior Pgp inhibitors have shown very limited clinical success because these agents have relatively low potency and high toxicity...
October 4, 2016: Biochimica et Biophysica Acta
Hsien-Jen Cheng, Te-Haw Wu, Chih-Te Chien, Hai-Wei Tu, Ting-Shan Cha, Shu-Yi Lin
Despite nanoparticulate platinum (nano-Pt) has been validated to be acting as a platinum-based prodrug for anticancer therapy, the key factor in controlling its cytotoxicity remains to be clarified. In this study, it is found that the corrosion susceptibility of nano-Pt can be triggered by inducing the oxidization of superficial Pt atoms, which can kill both cisplatin-sensitive/resistance cancer cells. Direct evidence in the oxidization of superficial Pt atoms is validated to observe the formation of platinum oxides by X-ray absorption spectroscopy...
September 22, 2016: Small
Guoke Liu, Xiaoyu Fan, Min Tang, Rui Chen, Hao Wang, Rongjie Jia, Xuyu Zhou, Wei Jing, Huajing Wang, Yang Yang, Fan Yin, Huafeng Wei, Bohua Li, Jian Zhao
Hepatocellular carcinoma (HCC) is a major health burden worldwide for its high incidence and mortality. Osteopontin (OPN) is a chemokine-like, matricellular phosphoglycoprotein whose expression is elevated in various types of cancer including HCC. OPN has been shown to be involved in tumorigenesis, chemo-resistance, metastasis and sustaining stem-like properties of cancer cells. Autophagy is a cellular process by which cytoplasmic components are degraded and recycled for maintaining cellular homeostasis. There is increasing evidence supports that autophagy plays a critical role for stem-like properties and chemo-resistance of cancer cells...
October 1, 2016: Cancer Letters
Zhiyang Wang, Shuai Liu, Kejia Ding, Sentai Ding, Chensheng Li, Jiaju Lu, Dexuan Gao, Tong Zhang, Dongbin Bi
Renal cell carcinoma (RCC) accounts for 3 % of all adult malignancies and is the most lethal urological cancer. Livin is a member of the inhibitor of apoptosis protein (IAP) family, which is associated with tumor resistance to radiotherapy and chemotherapy. Clinical data also showed that patients with high tumor grades and stages have higher expression levels of Livin in RCC cells. Autophagy is a survival mechanism activated in response to nutrient deprivation. A possible role of Livin in the autophagy of RCC cells has not been investigated; therefore, this pioneer study was carried out...
September 27, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Andrew Oliveira Silva, Eloisa Dalsin, Giovana Ravizzoni Onzi, Eduardo Cremonese Filippi-Chiela, Guido Lenz
Chemotherapy acts on cancer cells by producing multiple effects on a cell population including cell cycle arrest, necrosis, apoptosis and senescence. However, often a subpopulation of cells survives and the behavior of this subpopulation, which is responsible for cancer recurrence, remains obscure. Here we investigated the in vitro short- and long-term responses of six glioblastoma cell lines to clinically relevant doses of temozolomide for 5 days followed by 23 days of recovery, mimicking the standard schedule used in glioblastoma patient for this drug...
September 23, 2016: Experimental Cell Research
TianJun Chen, Hui Ren, Asmitanand Thakur, Tian Yang, Yang Li, Shuo Zhang, Ting Wang, MingWei Chen
Klotho is originally discovered as an anti-aging gene and recently identified as a tumor suppressor in various human cancers. Drug resistance is a major obstacle to affect the treatment of chemotherapy. In the present study, we explore the role of klotho on drug resistance in human lung cancers and investigate the mechanism of klotho on drug resistance in lung cancer cells. First, we detected a panel of six human lung cancer cell lines, including H460, SK-MES-1, cisplatin (DDP)-resistant A549/DDP, its parental subline A549, docetaxel (DTX)-resistant SPC-A-1/DTX, and SPC-A-1 by western blotting analysis...
September 23, 2016: DNA and Cell Biology
Bo-Wen Lin, Cheng-Chen Gong, Hai-Fei Song, Ying-Yu Cui
Anthocyanins are a class of water-soluble flavonoids, which show some pharmacological effects, such as prevention of cardiovascular disease, obesity control and anti-tumour activity. Their potential anti-tumour effects are reported to be based mainly on antioxidant, anti-inflammation, anti-mutagenesis, induction of differentiation, inhibiting proliferation by modulating signal transduction pathways, inducing cell cycle arrest and stimulating apoptosis or autophagy of cancer cells; anti-invasion and anti-metastasis; reversing drug resistance of cancer cells; and increasing their sensitivity to chemotherapy...
September 20, 2016: British Journal of Pharmacology
María José García Cebrián, Monika Bauden, Roland Andersson, Stefan Holdenrieder, Daniel Ansari
Pancreatic cancer has a dismal prognosis and there is an increasing and unmet need to identify better diagnostic and therapeutic targets in order to ameliorate the course of the disease. HMGB1, a nuclear DNA-binding protein that acts as a transcription factor, is currently in the limelight. HMGB1 exhibits a dual role in pancreatic cancer; when intracellular, it acts as an anti-tumor protein stabilizing the genome, whereas extracellular HMGB1 behaves as a pro-tumor protein with cytokine, chemokine and growth factor functions...
September 2016: Anticancer Research
Maria Rovithi, Richard R de Haas, Richard J Honeywell, Dennis Poel, Godefridus J Peters, Arjan W Griffioen, Henk M W Verheul
BACKGROUND: Increased exposure to multitargeted kinase inhibitor sunitinib is associated with improved outcome, emphasizing the importance of maintaining adequate dosing and drug levels. The currently approved schedule (50 mg daily, four weeks on, two weeks off) precludes further dose-intensification. Recent data suggest that sunitinib, although initially developed as an antiangiogenic agent, has direct antitumor activity. METHODS: In this study, we tested whether a chemotherapy-like schedule of pulsatile high dose sunitinib would result in improved antitumor activity...
2016: Journal of Experimental & Clinical Cancer Research: CR
Jennifer Nguyen, Luxi Chen, Dhiraj Kumar, Jiyong Lee
Some cancer cells are resistant to apoptosis, rendering them irresponsive towards apoptosis-inducing chemotherapy drugs. Another mode of action to kill these apoptosis-defective cells is essential and autophagy, a dynamic process that degrades cytoplasmic contents for cellular maintenance, has been considered as one of the alternate routes. A small molecule inducer of autophagy, autophagonizer was reported to induce cell death through a novel process that is independent of extrinsic apoptosis and the normal signaling pathways of autophagy...
October 1, 2016: Bioorganic & Medicinal Chemistry Letters
Renxiong Wei, Gang Cao, Zhouming Deng, Jiajia Su, Lin Cai
Acquisition of drug-resistant phenotypes is often associated with chemotherapy in osteosarcoma. A number of studies have demonstrated a critical role for autophagy in osteosarcoma development, therapy and drug resistance. However, the molecular mechanisms underlying the autophagy-mediated chemotherapy resistance of osteosarcoma cells remain largely unknown. In the present study, we determined the autophagy and microRNA-140 (miR-140-5p, miRBase ID: MIMAT0000431) expression induced by chemotherapeutic drugs in osteosarcoma cells...
October 2016: Bioscience Reports
Sofia Avnet, Silvia Lemma, Margherita Cortini, Paola Pellegrini, Francesca Perut, Nicoletta Zini, Katsuyuki Kusuzaki, Tokuhiro Chano, Giulia Grisendi, Massimo Dominici, Angelo De Milito, Nicola Baldini
Current therapy of osteosarcoma (OS), the most common primary bone malignancy, is based on a combination of surgery and chemotherapy. Multidrug resistance mediated by P-glycoprotein (P-gp) overexpression has been previously associated with treatment failure and progression of OS, although other mechanisms may also play a role. We considered the typical acidic extracellular pH (pHe) of sarcomas, and found that doxorubicin (DXR) cytotoxicity is reduced in P-gp negative OS cells cultured at pHe 6.5 compared to standard 7...
August 22, 2016: Oncotarget
Shu-Mei Chen, Ying-Ying Li, Chiao-Hui Tu, Nicole Salazar, Yuan-Yun Tseng, Shiang-Fu Huang, Ling-Ling Hsieh, Tai-Ngar Lui
BACKGROUND: Medulloblastoma (MB) is the most common pediatric primary malignant brain tumor. Approximately one-third of MB patients succumb to treatment failure and some survivors suffer detrimental side effects. Hence, the purpose of this study is to explore new therapeutic regimens to overcome chemotherapeutic agent resistance or reduce chemotherapy-induced toxicity. METHODS: We detected the expression of inhibitors of apoptosis proteins (IAPs) in MB and CD133+ MB cell lines and MB tissues using immunoblotting and immunohistochemical staining...
2016: PloS One
Chao Ji, Ziping Zhang, Lihong Chen, Kunli Zhou, Dongjun Li, Ping Wang, Shuying Huang, Ting Gong, Bo Cheng
Melanoma is one of the deadliest skin cancers and accounts for most skin-related deaths due to strong resistance to chemotherapy drugs. In the present study, we investigated the mechanisms of dabrafenib-induced drug resistance in human melanoma cell lines A375 and MEL624. Our studies support that both endoplasmic reticulum (ER) stress and autophagy were induced in the melanoma cells after the treatment with dabrafenib. In addition, ER stress-induced autophagy protects melanoma cells from the toxicity of dabrafenib...
2016: Drug Design, Development and Therapy
Federico Pietrocola, Jonathan Pol, Erika Vacchelli, Elisa E Baracco, Sarah Levesque, Francesca Castoldi, Maria Chiara Maiuri, Frank Madeo, Guido Kroemer
Cancer can be viewed in 2 rather distinct ways, namely (i) as a cell-autonomous disease in which malignant cells have escaped control from cell-intrinsic barriers against proliferation and dissemination or (ii) as a systemic disease that involves failing immune control of aberrant cells. Since macroautophagy/autophagy generally increases the fitness of cells as well as their resistance against endogenous or iatrogenic (i.e., relating to illness due to medical intervention) stress, it has been widely proposed that inhibition of autophagy would constitute a valid strategy for sensitizing cancer cells to chemotherapy or radiotherapy...
October 2, 2016: Autophagy
Han Zhang, Zheng Chen, Roberto N Miranda, L Jeffrey Medeiros, Nami McCarty
Expression of the transglutaminase TG2 has been linked to constitutive activation of NF-kB and chemotherapy resistance in mantle cell lymphoma (MCL) cells. TG2 forms complexes with NF-kB components, but mechanistic insights that could be used to leverage therapeutic responses has been lacking. In the present study, we address this issue with the discovery of an unexpected role for TG2 in triggering autophagy in drug-resistant MCL cells through induction of IL-6. CRISPR-mediated silencing of TG2 delayed apoptosis while overexpressing TG2 enhanced tumor progression...
August 3, 2016: Cancer Research
R Ojha, S K Singh, S Bhattacharyya
BACKGROUND: Autophagy is a critical process in acquiring drug resistance in solid tumors. However, the mechanisms by which autophagy modulate resistance to chemotherapy in bladder cancer remains poorly understood. MATERIAL AND METHODS: We have established cisplatin resistant patient derived primary cultured cells as well as T24 bladder cancer cells. The autophagy flux as well as the effect of chemotherapeutic agents, gemcitabine (GC) and mitomycin (MM) were evaluated in these cells...
November 2016: Biochimica et Biophysica Acta
Teng-Fei Fan, Tian-Fu Wu, Lin-Lin Bu, Si-Rui Ma, Yi-Cun Li, Liang Mao, Zhi-Jun Sun, Wen-Feng Zhang
Chemotherapy is an effective weapon in the battle against cancer, but numerous cancer patients are either not sensitive to chemotherapy or develop drug resistance to current chemotherapy regimens. Therefore, an effective chemotherapy mechanism that enhances tumor sensitivity to chemotherapeutics is urgently needed. The aim of the present study was to determine the antitumor activity of dihydromyricetin (DHM) on head and neck squamous cell carcinoma (HNSCC) and its underlying mechanisms. We demonstrated that DHM can markedly induce apoptotic cell death and autophagy in HNSCC cells...
July 25, 2016: Oncotarget
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