We present a strategy of co-delivery of apoptotic AVPI peptide and p53 DNA as apoptosis-induction adjuvant therapy for combating the resistant breast cancer. Promoting apoptosis is an important method to sensitize the resistant cells, thereby achieving successful treatment for MDR cancer. Defective apoptosis in cancer cells is a key factor responsible for chemoresistance or radioresistance. The cytotoxic potency in vitro/ex vivo and the remarkable ability to overcome multidrug resistance propose KP772 as a promising candidate drug for antileukemic therapy, especially of drug-refractory malignancies.ĭrug resistance becomes a formidable challenge against effective cancer therapy. In combination with vincristine, doxorubicin and cytarabine, synergistic effects were observed in BJAB cells. Remarkably, KP772 overcame drug resistance to doxorubicin and vincristine in vitro, and the apoptotic effect in resistant cells was even superior to that in non-resistant parental cells. mRNA expression profiling revealed an upregulation of the BH3-only Bcl-2 protein Harakiri in the course of KP772-induced apoptosis. KP772 induces apoptosis independently of Bcl-2, Smac, and the CD95 receptor and is also effective in caspase 3-deficient MCF7 cells, indicating that apoptosis is partly triggered independently of caspase 3. Primary AML cells were also sensitive to KP772, whereas daunorubicin showed no significant effect. KP772 inhibited proliferation and induced apoptosis in various leukemia and lymphoma cell lines in a concentration-dependent manner (LC 50 = 1–2.5 µM). Real-time PCR was used to gain insight into the mechanism of apoptosis induction.
The ability to overcome drug resistances was investigated in doxorubicin- and vincristine-resistant cell lines. Antiproliferative and apoptotic activities of KP772 were tested in leukemia, lymphoma and solid tumor cell lines as well as primary leukemia cells (isolated from the bone marrow of a child with acute myeloid leukemia (AML). Tris (1,10-phenanthroline) tris (thiocyanato-κ N )lanthanum(III) (KP772) is an experimental antineoplastic agent to which multidrug-resistant cell models have shown hypersensitivity. Despite high cure rates in pediatric patients with acute leukemia, development of resistance limits the efficacy of antileukemic therapy.
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