Oguzhan Doganlar, Zeynep Banu Doganlar, Suat Erdogan, Emre Delen
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引用次数: 0
Abstract
Combinations of the well-known antineoplastic agents 5-fluorouracil (5-Fu), cisplatin, and paclitaxel are employed to increase radiotherapy/immunotherapy efficacy against persistent and resistant tumors. However, data remains needed on the hormetic, chronic, and long-term side effects of these aggressive combination chemotherapies. Here we investigated cellular and molecular responses associated with these combined agents, and their potential to induce multi-drug resistance against the temozolomide (TMZ) and etoposide (EP) used in glioblastoma maintenance treatment. We analyzed resistance and survival signals in U87 MG cells using molecular probes, fluorescent staining, qRT-PCR, and immunoblot. Repeated treatment with combined 5-Fu, cisplatin, and paclitaxel induced cross-resistance against TMZ and EP. Resistant cells exhibited elevated gene/protein expression of MRP1/ABCC1, ABCC2, BRCP/ABCG2, and GST. Moreover, they managed oxidative stress, cell cycle, apoptosis, and autophagy signaling to ensure survival. In these groups TMZ and etoposide efficiency dramatically reduced. Our result suggests that combined high-dose treatments of classical antineoplastic agents to sensitize tumors may trigger multi-drug resistance and inhibit maintenance treatment. When deciding on antineoplastic combination therapy for persistent/resistant glioblastoma, we recommend analyzing the long-term hormetic and chronic effects on cross-resistance and multi-drug resistance in primary cell cultures from patients. See also the Graphical Abstract(Fig. 1).
期刊介绍:
EXCLI Journal publishes original research reports, authoritative reviews and case reports of experimental and clinical sciences.
The journal is particularly keen to keep a broad view of science and technology, and therefore welcomes papers which bridge disciplines and may not suit the narrow specialism of other journals. Although the general emphasis is on biological sciences, studies from the following fields are explicitly encouraged (alphabetical order):
aging research, behavioral sciences, biochemistry, cell biology, chemistry including analytical chemistry, clinical and preclinical studies, drug development, environmental health, ergonomics, forensic medicine, genetics, hepatology and gastroenterology, immunology, neurosciences, occupational medicine, oncology and cancer research, pharmacology, proteomics, psychiatric research, psychology, systems biology, toxicology