bromotetrandrine and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Multidrug resistance in cancer is a major obstacle for clinical therapeutics, and is the reason for 90% of treatment failures. This study investigated the efficiency of novel multifunctional Fe(3)O(4) magnetic nanoparticles (Fe(3)O(4)-MNP) combined with chemotherapy and hyperthermia for overcoming multidrug resistance in an in vivo model of leukemia.. Nude mice with tumor xenografts were randomly divided into a control group, and the treatment groups were allocated to receive daunorubicin, 5-bromotetrandrine (5-BrTet) and daunorubicin, Fe(3)O(4)-MNP, and Fe(3)O(4)-MNP coloaded with daunorubicin and 5-bromotetrandrine (Fe(3)O(4)-MNP-DNR-5-BrTet), with hyperthermia in an alternating magnetic field. We investigated tumor volume and pathology, as well as P-glycoprotein, Bcl-2, Bax, and caspase-3 protein expression to elucidate the effect of multimodal treatment on overcoming multidrug resistance.. Fe(3)O(4)-MNP played a role in increasing tumor temperature during hyperthermia. Tumors became significantly smaller, and apoptosis of cells was observed in both the Fe(3)O(4)-MNP and Fe(3)O(4)-MNP-DNR-5-BrTet groups, especially in the Fe(3)O(4)-MNP-DNR-5-BrTet group, while tumor volumes in the other groups had increased after treatment for 12 days. Furthermore, Fe(3)O(4)-MNP-DNR-5-BrTet with hyperthermia noticeably decreased P-glycoprotein and Bcl-2 expression, and markedly increased Bax and caspase-3 expression.. Fe(3)O(4)-MNP-DNR-5-BrTet with hyperthermia may be a potential approach for reversal of multidrug resistance in the treatment of leukemia.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; bcl-2-Associated X Protein; Benzylisoquinolines; Caspase 3; Combined Modality Therapy; Daunorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Hyperthermia, Induced; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Magnetic Field Therapy; Magnetite Nanoparticles; Mice; Mice, Inbred BALB C; Mice, Nude; Nanomedicine; Proto-Oncogene Proteins c-bcl-2; Xenograft Model Antitumor Assays

This study aims to evaluate the multidrug resistance (MDR) reversal activity by magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4) and 5-bromotetrandrine (BrTet) MDR cell line K562/A02 solitarily or symphysially. The proliferation of K562 and K562/A02 cells and the cytotoxicity on peripheral blood mononuclear cells (PMBCs) were evaluated by MTT assay. Cellular accumulation of daunorubicin (DNR) was analyzed by flow cytometry. Real-time polymerase chain reaction and Western blotting analyses were performed to examine the mRNA and protein levels of mdr1, respectively. The results showed that the combination of MNPs-Fe3O4 and BrTet with effective concentrations significantly increased cytotoxicity against MDR cell line K562/A02. Both BrTet and MNPs-Fe3O4 increased the intracellular DNR accumulation in the K562/A02 cell line, and downregulated the level of mdr1 gene and expression of P-glycoprotein. Furthermore, the combination did not have significant cytotoxicity in PMBCs. We propose that MNPs-Fe3O4 conjugated with DNR and BrTet probably have synergetic effects on MDR reversal.

Topics: Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Base Sequence; Benzylisoquinolines; Cell Survival; Daunorubicin; Down-Regulation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Ferrosoferric Oxide; Genes, MDR; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Magnetics; Metal Nanoparticles; Nanomedicine; RNA, Messenger; RNA, Neoplasm