Book ChapterDOI
Mechanisms of multidrug resistance in cancer.
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TLDR
Identifying genes and mechanisms critical to the development of MDR in vivo and establishing a reliable method for analyzing clinical samples could help to predict theDevelopment of resistance and lead to treatments designed to circumvent it.Abstract:
The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Resistance exists against every effective anticancer drug and can develop by numerous mechanisms including decreased drug uptake, increased drug efflux, activation of detoxifying systems, activation of DNA repair mechanisms, evasion of drug-induced apoptosis, etc. In the first part of this chapter, we briefly summarize the current knowledge on individual cellular mechanisms responsible for MDR, with a special emphasis on ATP-binding cassette transporters, perhaps the main theme of this textbook. Although extensive work has been done to characterize MDR mechanisms in vitro, the translation of this knowledge to the clinic has not been crowned with success. Therefore, identifying genes and mechanisms critical to the development of MDR in vivo and establishing a reliable method for analyzing clinical samples could help to predict the development of resistance and lead to treatments designed to circumvent it. Our thoughts about translational research needed to achieve significant progress in the understanding of this complex phenomenon are therefore discussed in a third section. The pleotropic response of cancer cells to chemotherapy is summarized in a concluding diagram.read more
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Journal ArticleDOI
Atypical Cell Populations Associated with Acquired Resistance to Cytostatics and Cancer Stem Cell Features: The Role of Mitochondria in Nuclear Encapsulation
David Diaz-Carballo,Sebastian Gustmann,Holger Jastrow,Ali Haydar Acikelli,Philip Dammann,Jacqueline Klein,Ulrike Dembinski,Walter Bardenheuer,Sascha Malak,Marcos J. Araúzo-Bravo,Beate Schultheis,Constanze Aldinger,Dirk Strumberg +12 more
TL;DR: A portion of resistant tumor cells displayed nuclear encapsulation via mitochondrial aggregation in the nuclear perimeter in response to cytostatic insults, probably conferring imperviousness to drugs and long periods of dormancy until nuclear eclosion takes place.
Journal ArticleDOI
Knockdown of KLK11 reverses oxaliplatin resistance by inhibiting proliferation and activating apoptosis via suppressing the PI3K/AKT signal pathway in colorectal cancer cell
TL;DR: High expression of KLK11 in chemoresistant-patients and L-OHP-resistant cell lines was associated with lymph node metastases and histopathology, and Knockdown of KL kallikrein 11 can reverse L- OHP resistance by blocking PI3K/AKT signaling pathway.
Journal ArticleDOI
Kanglaite inhibits the expression of drug resistance genes through suppressing PVT1 in cisplatin-resistant gastric cancer cells.
TL;DR: KLT inhibited the expression of MDR1 and MRP1 via suppressing theexpression of PVT1, which suggested the potential mechanism of KLT involving in MDR in gastric cancer.
Journal ArticleDOI
Nitric oxide reverses drug resistance by inhibiting ATPase activity of p-glycoprotein in human multi-drug resistant cancer cells
TL;DR: The reversal of drug resistance is due to inhibition of the ATPase activity by nitric oxide, resulting in enhancement of the drug accumulation in the MDR cells, caused by formation of adriamycin-dependent toxic free radical species and subsequent cellular damage.
Journal ArticleDOI
Structural modifications of mitochondria-targeted chlorambucil alter cell death mechanism but preserve MDR evasion.
TL;DR: It is demonstrated that by tuning the alkylating activity of mt-Cbl via chemical modification, the rate of generation of protein adducts can be reduced, resulting in a shift of the cell death mechanism from necrosis to a more controlled apoptotic pathway.
References
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Journal ArticleDOI
ONCOMINE: A Cancer Microarray Database and Integrated Data-Mining Platform
Daniel R. Rhodes,Jianjun Yu,K. Shanker,Nandan P. Deshpande,Radhika Varambally,Debashis Ghosh,Terrence R. Barrette,Akhilesh Pandey,Arul M. Chinnaiyan +8 more
TL;DR: ONCOMINE is presented, a cancer microarray database and web-based data-mining platform aimed at facilitating discovery from genome-wide expression analyses and novel biomarkers and therapeutic targets are discovered.
Journal ArticleDOI
A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants.
TL;DR: Observations on the molecular basis of pleiotropic drug resistance are interpreted in terms of a model wherein certain surface glycoproteins control drug permeation by modulating the properties of hydrophobic membrane regions.
Journal ArticleDOI
Targeting multidrug resistance in cancer
Gergely Szakács,Jill K. Paterson,Joseph A. Ludwig,Catherine Booth-Genthe,Michael M. Gottesman +4 more
TL;DR: Various approaches to combating multidrug-resistant cancer are described, including the development of drugs that engage, evade or exploit efflux by ABC transporters.
Journal ArticleDOI
Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line
Susan P.C. Cole,Gabu Bhardwaj,James H. Gerlach,J. E. Mackie,Caroline E. Grant,Kurt C. Almquist,Alistair J. Stewart,Ebba U. Kurz,A. M. V. Duncan,Roger G. Deeley +9 more
TL;DR: Reversion to drug sensitivity was associated with loss of gene amplification and a marked decrease in mRNA expression, and the mRNA encodes a member of the ATP-binding cassette transmembrane transporter superfamily.
Journal ArticleDOI
A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity
Chava Kimchi-Sarfaty,Jung Mi Oh,In-Wha Kim,Zuben E. Sauna,Anna Maria Calcagno,Suresh V. Ambudkar,Michael M. Gottesman +6 more
TL;DR: It is hypothesized that the presence of a rare codon, marked by the synonymous polymorphism, affects the timing of cotranslational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.