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Cancer drug resistence

Mahfuz Al Mamun, Kaiissar Mannoor, Jun Cao, Firdausi Qadri, Xiaoyuan Song
Cancer stem cells (CSCs), a minor subpopulation of tumor bulks with self-renewal and seeding capacity to generate new tumors, posit a significant challenge to develop effective and long-lasting anti-cancer therapies. The emergence of drug resistance appears upon failure of chemo-/radiation therapy to eradicate the CSCs, thereby leading to CSC-mediated clinical relapse. Accumulating evidence suggests that transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells, drives cancer stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug resistance mechanisms like epithelial-to-mesenchymal transition (EMT), ATP-binding cassette (ABC) drug transporters, anti-apoptotic and/or pro-survival signaling, lineage plasticity, and evasion of immune surveillance...
December 5, 2018: Journal of Molecular Cell Biology
Tianqun Lang, Yiran Liu, Zhong Zheng, Wei Ran, Yihui Zhai, Qi Yin, Pengcheng Zhang, Yaping Li
Metastatic breast cancer may be resistant to chemo-immunotherapy due to the existence of cancer stem cells (CSC). And the control of particle size and drug release of a drug carrier for multidrug combination is a key issue influencing therapy effect. Here, a cocktail strategy is reported, in which chemotherapy against both bulk tumor cells and CSC and immune checkpoint blockade therapy are intergraded into one drug delivery system. The chemotherapeutic agent paclitaxel (PTX), the anti-CSC agent thioridazine (THZ), and the PD-1/PD-L1 inhibitor HY19991 (HY) are all incorporated into an enzyme/pH dual-sensitive nanoparticle with a micelle-liposome double-layer structure...
December 5, 2018: Advanced Materials
Z Mbese, B A Aderibigbe
BACKGROUND: Carvacrol is the major constituent of essential oils derived from plants. It exhibits antimicrobial, antioxidant, anticancer, anti-inflammatory, and anticholinesterase activity. The analogues of carvacrol can be prepared via selected synthetic routes, resulting in potent compounds. OBJECTIVE: Modifying carvacrol by the introduction of selected functionalities has the potential to enhance the biological activity of carvacrol. The functionalities on carvacrol such as the hydroxyl group, benzene ring and alkyl groups can be modified or used for hybridization with important pharmaceutical scaffolds...
December 4, 2018: Recent Patents on Anti-infective Drug Discovery
Ali Mahdi, Behrad Darvishi, Keivan Majidzadeh-A, Malihe Salehi, Leila Farahmand
It is now fully recognized that along with multiple physiological functions, angiogenesis is also involved in the fundamental process and pathobiology of several disorders including cancer. Recent studies have fully established the role of angiogenesis in cancer progression as well as invasion and metastasis. Consequently, many therapeutic agents such as monoclonal antibodies targeting angiogenesis pathway have been introduced in clinic with the hope for improving the outcomes of cancer therapy. Bevacizumab (Avastin®) was the first anti-vascular endothelial growth factor (VEGF) targeting monoclonal antibody developed with this purpose and soon received its accelerated US Food and Drug Administration (FDA) approval for treatment of patients with metastatic breast cancer in 2008...
December 4, 2018: Journal of Cellular Physiology
Yu Hua Quan, Ji-Young Lim, Byeong Hyeon Choi, Yeonho Choi, Young Ho Choi, Ji-Ho Park, Hyun Koo Kim
BACKGROUND: Chemoresistance remains a major challenge for effective chemotherapy of non-small-cell lung carcinoma (NSCLC). CD44 expression is related to the susceptibility of various cancer cell types to anticancer drugs. Here, we systematically investigated the CD44-dependent chemoresistance of NSCLC cells and developed a liposomal siRNA delivery system to overcome this chemoresistance by the self-targeted downregulation of CD44. METHODS: We confirmed the relationship between the expression of CD44 and the chemosensitivity of NSCLC cells using flow cytometry and MTT assay...
December 4, 2018: Cancer Chemotherapy and Pharmacology
Sammia Rehman, Ayesha Obaid, Anam Naz, Amjad Ali, Shahzina Kanwal, Jamil Ahmad
Background: A positive association between diabetes and breast cancer has been identified by various epidemiological and clinical studies. However, the possible molecular interactions between the two heterogeneous diseases have not been fully determined yet. There are several underlying mechanisms which may increase the risk of breast cancer in diabetic patients. Introduction: In this study, we focused on the role of O-GlcNAc transferase (OGT) enzyme in the regulation of phosphatidylinositol-3 kinase (PI3K) pathway through activation/deactivation of Akt protein...
2018: PeerJ
Steven K Libutti, Lawrence Tamarkin, Naris Nilubol
Although a number of new systemic therapeutic options in patients with advanced solid cancers have emerged due to the improved knowledge of molecular dysregulation in cancers, the durable, long-term, objective responses infrequently occur. This editorial article highlights the major limitation of current systemic therapy due to an inefficient drug delivery. While several mechanisms contributing to cancer drug resistance have been described, the common key barrier among solid cancers is the unique tumor microenvironment that causes the high interstitial fluid pressure (IFP)...
November 6, 2018: Oncotarget
Qinghua Wu, Jiri Patocka, Eugenie Nepovimova, Kamil Kuca
Beauvericin (BEA) is an emerging Fusarium mycotoxin that contaminates food and feeds globally. BEA biosynthesis is rapidly catalyzed by BEA synthetase through a nonribosomal, thiol-templated mechanism. This mycotoxin has cytotoxicity and is capable of increasing oxidative stress to induce cell apoptosis. Recently, large evidence further shows that this mycotoxin has a variety of biological activities and is being considered a potential candidate for medicinal and pesticide research. It is noteworthy that BEA is a potential anticancer agent since it can increase the intracellular Ca2+ levels and induce the cancer cell death through oxidative stress and apoptosis...
2018: Frontiers in Pharmacology
Hongbo Zhao, Yutang Huang, Jingjing Shi, Yi Dai, Lanxiang Wu, Honghao Zhou
Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), is used clinically as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC) with EGFR activating mutations, but the inevitable development of acquired resistance limits its efficacy. In up to 30-40% of NSCLC cases, the mechanism underlying acquired resistance remains unknown. ATP-binding cassette (ABC) transporters are a family of membrane proteins that can significantly influence the bioavailability of numerous drugs, and have confirmed to play an essential role in multidrug resistance (MDR) in cancer chemotherapy...
2018: Frontiers in Pharmacology
Jian Li, Kristen Kolberg, Ulrich Schlecht, Robert P St Onge, Ana Maria Aparicio, Joe Horecka, Ronald W Davis, Maureen E Hillenmeyer, Colin Jb Harvey
Multidrug resistance is highly conserved in mammalian, fungal, and bacterial cells, is characterized by resistance to several unrelated xenobiotics, and poses significant challenges to managing infections and many cancers. Eukaryotes use a highly conserved set of drug efflux transporters that confer pleiotropic drug resistance (PDR). To interrogate the regulation of this critical process, here we developed a small molecule-responsive biosensor that couples transcriptional induction of PDR genes to growth rate in the yeast Saccharomyces cerevisiae...
December 4, 2018: Journal of Biological Chemistry
Fatima Karzai, David VanderWeele, Ravi A Madan, Helen Owens, Lisa M Cordes, Amy Hankin, Anna Couvillon, Erin Nichols, Marijo Bilusic, Michael L Beshiri, Kathleen Kelly, Venkatesh Krishnasamy, Sunmin Lee, Min-Jung Lee, Akira Yuno, Jane B Trepel, Maria J Merino, Ryan Dittamore, Jennifer Marté, Renee N Donahue, Jeffrey Schlom, Keith J Killian, Paul S Meltzer, Seth M Steinberg, James L Gulley, Jung-Min Lee, William L Dahut
BACKGROUND: Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC)...
December 4, 2018: Journal for Immunotherapy of Cancer
Agnieszka Owczarczyk-Saczonek, Lesław Bernard Lahuta, Magdalena Ligor, Waldemar Placek, Ryszard Józef Górecki, Bogusław Buszewski
INTRODUCTION: Myo -inositol and its derivatives cyclitols play an important role in the processes of cell regulation, signal transduction, osmoregulation, and ion channel physiology, and are a component of the cell membrane. Free cyclitols present in food or released during the degradation of galactosyl cyclitols by bacteria (in digestive tract) show some physiological benefits. AIM: The aim of this paper is to present and analyze the documented data about curative and healing properties of cyclitols...
December 3, 2018: Nutrients
Malgorzata Czyz
Hepatocyte growth factor (HGF)/ mesenchymal-epithelial transition factor (c-MET) signaling is involved in complex cellular programs that are important for embryonic development and tissue regeneration, but its activity is also utilized by cancer cells during tumor progression. HGF and c-MET usually mediate heterotypic cell⁻cell interactions, such as epithelial⁻mesenchymal, including tumor⁻stroma interactions. In the skin, dermal fibroblasts are the main source of HGF. The presence of c-MET on keratinocytes is crucial for wound healing in the skin...
December 3, 2018: International Journal of Molecular Sciences
Rosamaria Lappano, Yves Jacquot, Marcello Maggiolini
Breast cancer is the most prevalent cancer found in women living in developed countries. Endocrine therapy is the mainstay of treatment for hormone-responsive breast tumors (about 70% of all breast cancers) and implies the use of selective estrogen receptor modulators and aromatase inhibitors. In contrast, triple-negative breast cancer (TNBC), a highly heterogeneous disease that may account for up to 24% of all newly diagnosed cases, is hormone-independent and characterized by a poor prognosis. As drug resistance is common in all breast cancer subtypes despite the different treatment modalities, novel therapies targeting signaling transduction pathways involved in the processes of breast carcinogenesis, tumor promotion and metastasis have been subject to accurate consideration...
December 2, 2018: International Journal of Molecular Sciences
Christopher T Lucido, W Keith Miskimins, Paola D Vermeer
Tumor cell metabolism differs from that of normal cells, conferring tumors with metabolic advantages but affording opportunities for therapeutic intervention. Accordingly, metabolism-targeting therapies have shown promise. However, drugs targeting singular metabolic pathways display limited efficacy, in part due to the tumor's ability to compensate by using other metabolic pathways to meet energy and growth demands. Thus, it is critical to identify novel combinations of metabolism-targeting drugs to improve therapeutic efficacy in the face of compensatory cellular response mechanisms...
November 30, 2018: Cancers
Sanam Sadreddini, Behzad Baradaran, Ali Aghebati-Maleki, Sevil Sadreddini, Dariush Shanehbandi, Ali Fotouhi, Leili Aghebati-Maleki
Among the main promising systems to triggering therapeutic antitumor immunity is the blockade of immune checkpoints. Immune checkpoint pathways regulate the control and eradication of infections, malignancies, and resistance against a host of autoantigens. Initiation point of the immune response is T cells, which have a critical role in this pathway. As several immune checkpoints are initiated by ligand-receptor interactions, they can be freely blocked by antibodies or modulated by recombinant forms of ligands or receptors...
December 3, 2018: Journal of Cellular Physiology
A K Eichelmann, C Matuszcak, K Lindner, J Haier, D J Hussey, R Hummel
miRNAs play a crucial role in cancer development and progression. However, results on the impact of miRNAs on drug sensitivity and tumor biology vary, and most studies to date focussed on either increasing or decreasing miRNA expression levels. Therefore, the current study investigated the role of different expression levels of miR-130a-3p and miR-148a-3p on drug resistance and tumor biology in four esophageal squamous cell carcinoma cell lines. Interestingly, up- and downregulation of both miRNAs significantly increased sensitivity towards chemotherapy...
December 3, 2018: Scientific Reports
Jona Kayser, Carl F Schreck, Matti Gralka, Diana Fusco, Oskar Hallatschek
Many cellular populations are tightly packed, such as microbial colonies and biofilms, or tissues and tumours in multicellular organisms. The movement of one cell in these crowded assemblages requires motion of others, so that cell displacements are correlated over many cell diameters. Whenever movement is important for survival or growth, these correlated rearrangements could couple the evolutionary fate of different lineages. However, little is known about the interplay between mechanical forces and evolution in dense cellular populations...
December 3, 2018: Nature Ecology & Evolution
Davide Zella, Sabrina Curreli, Francesca Benedetti, Selvi Krishnan, Fiorenza Cocchi, Olga S Latinovic, Frank Denaro, Fabio Romerio, Muhammad Djavani, Man E Charurat, Joseph L Bryant, Hervé Tettelin, Robert C Gallo
We isolated a strain of human mycoplasma that promotes lymphomagenesis in SCID mice, pointing to a p53-dependent mechanism similar to lymphomagenesis in uninfected p53-/- SCID mice. Additionally, mycoplasma infection in vitro reduces p53 activity. Immunoprecipitation of p53 in mycoplasma-infected cells identified several mycoplasma proteins, including DnaK, a member of the Hsp70 chaperon family. We focused on DnaK because of its ability to interact with proteins. We demonstrate that mycoplasma DnaK interacts with and reduces the activities of human proteins involved in critical cellular pathways, including DNA-PK and PARP1, which are required for efficient DNA repair, and binds to USP10 (a key p53 regulator), impairing p53-dependent anticancer functions...
December 3, 2018: Proceedings of the National Academy of Sciences of the United States of America
You Zhou, Xiao Zheng, Bin Xu, Lujun Chen, Qi Wang, Haifeng Deng, Jingting Jiang
Circular RNAs (circRNAs) were recently reported to be involved in the pathogenesis of Non-small cell lung cancer (NSCLC), however, the molecular mechanisms of circRNAs in cell proliferation, invasion and TKI drug resistance remain largely undetermined. Here, we identified hsa_circ_0004015 was upregulated in NSCLC tissues, and was associated with the poor overall survival rate of NSCLC patients. Knockdown of hsa_circ_0004015 significantly decreased cell viability, proliferation, and invasion, whereas overexpression exhibited opposed effects in vivo and in vitro...
November 30, 2018: Biochemical and Biophysical Research Communications
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