Fe3O4 nanoparticles with daunorubicin induce apoptosis through caspase 8-PARP pathway and inhibit K562 leukemia cell-induced tumor growth in vivo.

Nanomaterials can enhance the delivery and treatment efficiency of anticancer drugs, but the mechanisms of the tumor-reducing activity of ferrous-ferric oxide (Fe(3)O(4)) nanoparticles (NPs) with daunorubicin (DNR) have not been established. Here we investigate the synergistic effects of Fe(3)O(4) NPs with DNR on the induction of apoptosis using K562 leukemia cells. Fe(3)O(4) NPs increased the ability of DNR to induce apoptosis in both adriamycin-sensitive and adriamycin-resistant K562 cells through the caspase 8-poly(ADP-ribose) polymerase pathway. Fe(3)O(4) NPs combined with DNR also effectively inhibited the tumor growth induced by the inoculation of K562 cells into nude mice. The increased cell apoptotic rate was closely correlated with the enhanced inhibition of tumor growth. Biodistribution studies in xenograft tumors indicated that Fe(3)O(4) NPs could be potentially excreted from the body via the gastrointestinal system. In conclusion, our study suggests that Fe(3)O(4) NPs combined with anticancer drugs could serve as a better alternative for targeted therapeutic approaches to cancer treatments.

[Effect of Chromosomal Karyotype on the Prognosis of Patients with Acute Promyelocytic Leukemia in Condition of the Maintenance Treatment Based on Arsenic Trioxide].

OBJECTIVE: To investigate the effect of chromosomal karyotype on the prognosis of patients with acute promyelocytic leukemia (APL) in condition of the maintenance treatment based on arsenic trioxide. METHODS: The patients with acute promyelocytic leukemia for last 12 years in our hospital were retrospectively collected. The patients mainly treated with arsenic trioxide in maintenance protocol were selected and followed up. All the patients were divided into 3 groups according to cytogenetic data: single t (15; 17) group, t (15; 17) with additional chromosomal abnormality (ACA) group, and normal karyotype group. Then, the prognostic significance of ACAs and complex karyotype were investigated in APL patients. RESULTS: There were 57 cases in the single t (15; 17) group, in which 8 cases died in the first month after induction treatment with early mortality rate of 14%. There were 21 patients in t (15; 17) with ACA group, in which 4 cases died in the first month with early mortality rate of 19%. There were 15 cases in normal chromosome group, in which 5 cases died in the first month with the early mortality rate of 33.3%. There was no statistical difference in the early mortality among 3 groups. All the remaining 76 patients achieved complete hematological remission. These patients were followed up. The median follow-up time was 43.9 months. Among them, only 2 patients in single t (15; 17) group and 1 patient in t (15; 17) with ACA group relapsed. No patient relapsed in normal karyotype group. The relapse rate was 3.5% in single t (15; 17) group and 4.2% in t (15; 17) with ACA group, respectively. There was no statistical difference in the overall survival and disease-free survival rates among 3 groups. Further analysis showed that the patients with complex chromosome karyotypes had lower relapse-free survival rates, but overall survival rates were not significantly different in 3 group. CONCLUSION: In general, ACA can not affect the prognosis of patients with acute promyelocytic leukemia in condition of the maintenance treatment based on arsenic trioxide, but the complex chromosomal karyotype may reduce the relapse-free survival rates.

Daunorubicin-loaded magnetic nanoparticles of Fe(3)O(4) greatly enhance the responses of multidrug-resistant K562 leukemic cells in a nude mouse xenograft model to chemotherapy.

Multidrug resistance (MDR) plays a major role in the failure of cancer chemotherapy. Since Fe(3)O(4)-magnetic nanoparticle loaded with daunorubicin (DNR) can overcome multidrug-resistance of K562 cells in vitro, the effect of Fe(3)O(4)-magnetic nanoparticle loaded with DNR on multidrug-resistant K562 cells was studied in vivo, the K562-n and its MDR counterpart K562-n/VCR cells were inoculated subcutaneously into both sides of the back of nude mice to establish a human leukemia xenograft model. The mice were randomly divided into group A receiving normal saline, group B receiving DNR, group C receiving Fe(3)O(4)-magnetic nanoparticle, group D receiving Fe(3)O(4)-magnetic nanoparticle loaded with DNR and group E receiving Fe(3)O(4)-magnetic nanoparticle containing DNR with a magnetic field built on the surface of the tumor tissue. The tumor volume was measured on the day 1, 5, 9, 13, 17 and 21 after the first treatment. Tumor tissues were isolated for examination of the expression of mdr-1 by reverse transcription polymerase chain reaction and Western blotting. The results showed that for K562-n/VCR tumor, the tumor volume was markedly lower in groups D and E than that in groups A, B and C. Pathological observation revealed that the tumor cells of group A and B grew well, some disseminated necrosis and some cells with karyorrhexis and karyopyknosis existed in group C. However, significant fracture, necrosis of cell and subsequently fibrosis were seen in group D and E. The transcription of mdr-1 gene in groups D and E was significantly lower than that in groups A, B and C (group D and E vs group A, B or C, p < 0.05). However, there were no differences about the protein expression of P-gp between these groups. The tumor volume of K562-n in groups C, D and E was markedly lower than that in groups A and B (group C, D and E vs group A or B, p < 0.05). Pathological observation showed that the tumor cell of group A and B grew well, and no obvious necrosis was observed. Significant fracture, necrosis of cell and subsequently fibrosis were seen in group C, D and E. It is concluded that DNR-loaded Fe(3)O(4) magnetic nanoparticles can suppress the growth of the MDR K562-n/VCR tumor in vivo, but can not further enhance its efficacy on the sensitive K562-n tumor as compared to DNR alone. The additional external magnetic field failed to further improve the antitumor effect in vivo.

Daunorubicin-loaded magnetic nanoparticles of Fe3O4 overcome multidrug resistance and induce apoptosis of K562-n/VCR cells in vivo.

Multidrug resistance (MDR) is a major obstacle to cancer chemotherapy. We evaluated the effect of daunorubicin (DNR)-loaded magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4) on K562-n/VCR cells in vivo. K562-n and its MDR counterpart K562-n/VCR cell were inoculated into nude mice subcutaneously. The mice were randomly divided into four groups: group A received normal saline, group B received DNR, group C received MNPs-Fe3O4, and group D received DNR-loaded MNPs-Fe3O4. For K562-n/VCR tumor, the weight was markedly lower in group D than that in groups A, B, and C. The transcriptions of Mdr-1 and Bcl-2 gene were significantly lower in group D than those in groups A, B, and C. The expression of Bcl-2 was lower in group D than those in groups A, B, and C, but there was no difference in the expression of P-glycoprotein. The transcriptions and expressions of Bax and caspase-3 in group D were increased significantly when compared with groups A, B, and C. In conclusion, DNR-loaded MNPs-Fe3O4 can overcome MDR in vivo.