3 research outputs found
Amplifikacja BCR-ABL ma istotne znaczenie w oporno艣ci na inhibitory kinazy tyrozynowj w linii kom贸rkowej K-562
An emerging problem in patients with chronic myeloid leukemia (CML) is increasing resistance to tyrosine kinase inhibitors (TKIs). To determine genetic and cellular mechanisms involved in the development of resistance to TKIs, nine imatinib-resistant cell lines were derived from K- 562 cell line followed by testing of drug sensitivity, multidrug resistance proteins and cytogenetic studies. In imatinib-resistant cell lines cross-resistance to daunorubicin, etoposide and cytarabine were observed whereas sensitivity to dasatinib, nilotinib, cyclophpsphamide, bortezomib and busulfan was preserved. Treatment with imatinib decreased PGP and LRP expression, however it did not significantly influence MRP1 expression. Amount of signals in FISH analysis from ABL, BCR and from fusion genes (BCR-ABL or ABL-BCR) was mostly higher in imatinib-resistant cell lines in comparison to parental K-562 cell line. We concluded that BCR-ABL amplification but not cellular sensitivity is the major mechanisms of resistance in K-562 cell line.Narastaj膮ca oporno艣膰 na inhibitory kinazy tyrozynowej (TKIs) jest niepokoj膮cym problemem u pacjent贸w z przewlek艂膮 bia艂aczka szpikow膮 (CML). Aby okre艣li膰 genetyczne i kom贸rkowe mechanizmy oporno艣ci na TKIs z linii K-562 wyhodowano 9 opornych na imatynib linii kom贸rkowych, w kt贸rych przeprowadzono badania: oporno艣ci na leki, ekspresji bia艂ek oporno艣ci kom贸rkowej oraz badania cytogenetyczne. W opornych na imatinib liniach kom贸rkowych stwierdzono krzy偶ow膮 oporno艣膰 na daunorubicyn臋, etopozyd i cytarabin臋, podczas gdy wra偶liwo艣膰 na dasatinib, nilotinib, cyklofosfamid, bortezomib i busulfan by艂a zachowana. Hodowla z imatinibem zmniejsza艂a ekspresj臋 bia艂ka PGP i LRP ale nie wyp艂ywa艂a na ekspresj臋 bia艂ka MRP1. W badaniu metod膮 FISH w liniach opornych na imatinib w por贸wnaniu do macierzystej linii K-562 obserwowano wi臋ksz膮 ilo艣膰 sygna艂贸w pochodz膮cych od gen贸w ABL, BCR oraz od gen贸w fuzyjnych (BCR-ABL i ABL-BCR). Przeprowadzone badania wskazuj膮, 偶e nie mechanizmy oporno艣ci kom贸rkowej ale amplifikacja sekwencji BCR-ABL, jest g艂贸wnym mechanizmem oporno艣ci na TKIs w linii K-562
Bcr-Abl Amplification Plays a Major Role in Resistance to Tyrosine Kinase Inhibitors in K-562 Cell Line
An emerging problem in patients with chronic myeloid leukemia (CML) is increasing resistance to tyrosine kinase inhibitors (TKIs). To determine genetic and cellular mechanisms involved in the development of resistance to TKIs, nine imatinib-resistant cell lines were derived from K- 562 cell line followed by testing of drug sensitivity, multidrug resistance proteins and cytogenetic studies. In imatinib-resistant cell lines cross-resistance to daunorubicin, etoposide and cytarabine were observed whereas sensitivity to dasatinib, nilotinib, cyclophpsphamide, bortezomib and busulfan was preserved. Treatment with imatinib decreased PGP and LRP expression, however it did not significantly influence MRP1 expression. Amount of signals in FISH analysis from ABL, BCR and from fusion genes (BCR-ABL or ABL-BCR) was mostly higher in imatinib-resistant cell lines in comparison to parental K-562 cell line. We concluded that BCR-ABL amplification but not cellular sensitivity is the major mechanisms of resistance in K-562 cell line.Narastaj膮ca oporno艣膰 na inhibitory kinazy tyrozynowej (TKIs) jest niepokoj膮cym problemem u pacjent贸w z przewlek艂膮 bia艂aczka szpikow膮 (CML). Aby okre艣li膰 genetyczne i kom贸rkowe mechanizmy oporno艣ci na TKIs z linii K-562 wyhodowano 9 opornych na imatynib linii kom贸rkowych, w kt贸rych przeprowadzono badania: oporno艣ci na leki, ekspresji bia艂ek oporno艣ci kom贸rkowej oraz badania cytogenetyczne. W opornych na imatinib liniach kom贸rkowych stwierdzono krzy偶ow膮 oporno艣膰 na daunorubicyn臋, etopozyd i cytarabin臋, podczas gdy wra偶liwo艣膰 na dasatinib, nilotinib, cyklofosfamid, bortezomib i busulfan by艂a zachowana. Hodowla z imatinibem zmniejsza艂a ekspresj臋 bia艂ka PGP i LRP ale nie wyp艂ywa艂a na ekspresj臋 bia艂ka MRP1. W badaniu metod膮 FISH w liniach opornych na imatinib w por贸wnaniu do macierzystej linii K-562 obserwowano wi臋ksz膮 ilo艣膰 sygna艂贸w pochodz膮cych od gen贸w ABL, BCR oraz od gen贸w fuzyjnych (BCR-ABL i ABL-BCR). Przeprowadzone badania wskazuj膮, 偶e nie mechanizmy oporno艣ci kom贸rkowej ale amplifikacja sekwencji BCR-ABL, jest g艂贸wnym mechanizmem oporno艣ci na TKIs w linii K-562
Upregulation of Succinate Dehydrogenase (SDHA) Contributes to Enhanced Bioenergetics of Ovarian Cancer Cells and Higher Sensitivity to Anti-Metabolic Agent Shikonin
We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is particularly prevalent in ovarian carcinoma and promotes highly metabolically active phenotype. Succinate dehydrogenase deficiency has been previously studied in some rare disorders. However, the role of SDHA upregulation and its impact on ovarian cancer metabolism has never been investigated, emphasizing the need for further research. We investigated the functional consequences of SDHA overexpression in ovarian cancer. Using proteomics approaches and biological assays, we interrogated protein content of metabolic pathways, cell proliferation, anchorage-independent growth, mitochondrial respiration, glycolytic function, and ATP production rates in those cells. Lastly, we performed a drug screening to identify agents specifically targeting the SDHA overexpressing tumor cells. We showed that SDHA overexpressing cells are characterized by enhanced energy metabolism, relying on both glycolysis and oxidative phosphorylation to meet their energy needs. In addition, SDHA-high phenotype was associated with cell vulnerability to glucose and glutamine deprivation, which led to a substantial reduction of ATP yield. We also identified an anti-metabolic compound shikonin with a potent efficacy against SDHA overexpressing ovarian cancer cells. Our data underline the unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which represents a new opportunity for therapeutic intervention