The truth is, Lyn more than expression, irrespective of Brc Abl, occurs in the K CML cell line and insome CML individuals .Moreover, in the subset of sufferers imatinib resistance just isn’t totally understood . Imatinib resistance is studied in four cell lines: AR, LAMA, K and KCL . AR cells are characterized by up regulation from the Bcr Abl protein related with amplification with the BCR ABL gene. Along with this mechanism, LAMA cells also more than express P gp thereby indicating that imatinib resistance occurs through no less than two mechanisms in these cells. Bcr Abl is not overexpressed in K cells, however the imatinib IC for inhibition of Bcr Abl autophosphorylation was greater in resistant clones . None on the afore reported mechanisms of resistance was detected in KCL cells . Interestingly, KCLS cells survive longer in the presence of imatinib than other sensitive cell lines suggesting that KCLS cells are intrinsically much less sensitive than other CML cells to imatinib .
In reality, it has been proven that M imatinib induces a marked reduce of Bcr Abl phosphorylation and within the all round expression of phosphotyrosine proteins in LAMA cells in contrast with K and KCLS cells . This observation suggests that K and KCL cells have an intrinsic resistance to imatinib, possible quite possibly related for the expression of many proteins implicated in drug resistance syk inhibitors and anti apoptotic exercise . A latest study showed that KCLR cells also have an elevated development rate and resistance to apoptosis . Additionally, KCLS cells have features standard of your quiescent hematopoietic Ph stem cells . In line with this observation, it has been shown that imatinib, in blend by using a farnesyltransferase inhibitor, induced KCLS development arrest but apoptosis was much less evident in KCL cells than in other CML cells . In a further research, autophosphorylation of Bcr Abl in KCLR cells was suppressed by imatinib, as occurs in KCLS cells, which suggests that KCLR cells have evolved an substitute usually means for survival that may bypass dependence around the major oncoprotein action .
Last but not least, imatinib did Ruxolitinib selleck not induce Bcr Abl up regulation or even a increased threshold for tyrosine kinase inhibition in KCLR cells . KCL cells are as a result a good model with which to achieve insights to the Bcr Abl independent mechanisms of imatinib resistance. It truly is noteworthy that a drug might possibly exert pleiotropic results on the amount of several proteins therefore resulting in adjustments in protein expression, post translational modifications, and protein protein interactions. Latest studies have examined the effects of imatinib on international protein expression and on global protein phosphorylation in Bcr Abl constructive cell lines.