Chromosomal instability confers intrinsic multidrug resistance.
Aneuploidy is associated with poor prognosis in solid tumors. Spontaneous chromosome missegregation events in aneuploid cells promote chromosomal instability (CIN) that may contribute to the acquisition of multidrug resistance in vitro and heighten risk for tumor relapse in animal models. Identification of distinct therapeutic agents that target tumor karyotypic complexity has important clinical implications. To identify distinct therapeutic approaches to specifically limit the growth of CIN tumors, we focused on a panel of colorectal cancer (CRC) cell lines, previously classified as either chromosomally unstable (CIN(+)) or diploid/near-diploid (CIN(-)), and treated them individually with a library of kinase inhibitors targeting components of signal transduction, cell cycle, and transmembrane receptor signaling pathways. CIN(+) cell lines displayed significant intrinsic multidrug resistance compared with CIN(-) cancer cell lines, and this seemed to be independent of somatic mutation status and proliferation rate. Confirming the association of CIN rather than ploidy status with multidrug resistance, tetraploid isogenic cells that had arisen from diploid cell lines displayed lower drug sensitivity than their diploid parental cells only with increasing chromosomal heterogeneity and isogenic cell line models of CIN(+) displayed multidrug resistance relative to their CIN(-) parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN(+) predicted worse progression-free or disease-free survival relative to patients with CIN(-) disease. Our results suggest that stratifying tumor responses according to CIN status should be considered within the context of clinical trials to minimize the confounding effects of tumor CIN status on drug sensitivity.
Molecular epidemiology of sequential outbreaks of Acinetobacter baumannii in an intensive care unit shows the emergence of carbapenem resistance.
The molecular epidemiology of multidrug-resistant Acinetobacter baumannii was investigated in the medical-surgical intensive care unit (ICU) of a university hospital in Italy during two window periods in which two sequential A. baumannii epidemics occurred. Genotype analysis by pulsed-field gel electrophoresis (PFGE) of A. baumannii isolates from 131 patients identified nine distinct PFGE patte...متن کامل
Revised manuscript AAC 01388 - 10 1 Efflux - Mediated Antibiotic Resistance in Acinetobacter spp . 2 3 4
24 Among Acinetobacter spp., A. baumannii is the most frequently implicated in nosocomial 25 infections, in particular in intensive care units. It was initially thought that multidrug 26 resistance (MDR) in this species was mainly due to horizontal acquisition of resistance genes. 27 However, it has become recently obvious that increased expression of chromosomal genes for 28 efflux systems pla...متن کامل
Current genetic and epigenetic theories of cancer-specific drug resistance do not adequately explain: (i) the karyotypic changes that coincide with resistance, (ii) the high rates at which cancer cells acquire and enhance resistance compared to the rates of conventional mutation, (iii) the wide ranges of resistance such as multidrug resistance, (iv) the frequent occurrence of intrinsic drug res...متن کامل
Treatment of infections is compromised worldwide by the emergence of bacteria that are resistant to multiple antibiotics. Although classically attributed to chromosomal mutations, resistance is most commonly associated with extrachromosomal elements acquired from other bacteria in the environment. These include different types of mobile DNA segments, such as plasmids, transposons, and integrons...متن کامل
CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction.
Chromosomal instability (CIN) has been implicated in multidrug resistance and the silencing of the ceramide transporter, CERT, promotes sensitization to diverse cytotoxics. An improved understanding of mechanisms governing multidrug sensitization might provide insight into pathways contributing to the death of CIN cancer cells. Using an integrative functional genomics approach, we find that CER...متن کامل