Abstract
Amongst all leukemias, Bcr-Abl positive chronic myelogenous leukemia (CML) confers resistance to native drug due to multi drug resistance and also resistance to p53 and fas ligand pathways. In the present study, we have investigated the efficacy of microtubule stabilizing paclitaxel loaded magnetic nanoparticles (pac-MNPs) to ascertain its cytotoxic effect on Bcr-Abl positive K562 cells. For active targeted therapy, pac-MNPs were functionalized with lectin glycoprotein which resulted in higher cellular uptake and lower IC50 value suggesting the efficacy of targeted delivery of paclitaxel. Both pac-MNPs and lectin conjugated pac-MNPs have a prolonged circulation time in serum suggesting increased bioavailability and therapeutics index of paclitaxel in vivo. Further, the molecular mechanism pertaining to pac-induced cytotoxicity was analyzed by studying the involvement of different apoptotic pathway proteins by immunoblotting and quantitative PCR. Our study revealed simultaneous activation of JNK pathway leading to Bcr-Abl instability and the extrinsic apoptotic pathway after pac-MNPs treatment in two Bcr-Abl positive cell lines. In addition, the MRI data suggested the potential application of MNPs as imaging agent. Thus our in vitro and in vivo results strongly suggested the pac-MNPs as a future prospective theranostic tool for leukemia therapy.
Highlights
Amongst the different types of leukemias, chronic myelogenous leukemia (CML) is a clonal malignancy of the hematopoietic stem cells that arises from a 9; 22 chromosomal translocation which fuses the ABL proto-oncogene to the BCR gene encoding the fusion protein p210Bcr-Abl [1,2]
Jun N-terminal kinases (JNKs) and p38 are only weakly activated by growth factors, but are highly activated in response to a variety of stress signals including tumor necrosis factor and their activation is most frequently associated with induction of apoptosis [3]
Here in this study, we have investigated the efficacy of paclitaxel loaded magnetic nanoparticles (MNPs) formulations functionalized with a targeting moiety lectin
Summary
Amongst the different types of leukemias, chronic myelogenous leukemia (CML) is a clonal malignancy of the hematopoietic stem cells that arises from a 9; 22 chromosomal translocation which fuses the ABL proto-oncogene to the BCR gene encoding the fusion protein p210Bcr-Abl [1,2]. The distinct MAPK members are the important signaling molecules in the control of cell proliferation and differentiation. These include extracellular signal-regulated kinases (ERKs), pAkt, stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs) and the p38 MAPK. In CML the Bcr-Abl gene enhances the cell proliferation by activating the ERK and pAkt pathways and by inhibiting the p38 and JNK pathways [1]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
