J Cancer 2014; 5(6):480-490. doi:10.7150/jca.8731 This issue
1. Department of Hematology, Jagiellonian University Medical College, Krakow, Poland
2. Department of Transplantology, Jagiellonian University Medical College, Krakow, Poland
3. Department of Gastroenterology, Hepatology and Infectious Diseases, Jagiellonian University Medical College, Krakow, Poland
4. Students' Scientific Society, Jagiellonian University Medical College, Krakow, Poland
5. Second Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland
Introduction. Geldanamycin (GA) is an ansamycin antibiotic that exhibits potent anti-neoplastic properties. The aim of this study was to assess the impact of GA and its derivatives on the growth and invasiveness of myeloma cell lines and CD138+ cells derived from the bone marrow of patients with multiple myeloma.
Materials and methods. We evaluated cell proliferation, survival, apoptosis, cell cycle of myeloma cells, and the expression of cell surface proteins after incubation with geldanamycin or its derivatives.
Results. GA and its analogs have an effect on myeloma cells by inhibiting their growth in a time and dose-dependent manner. Myeloma cell lines demonstrated decreased proliferation after incubation with 10 nM of GA or 100 nM GA analogs. The first significant effects of GA on U266 cells was observed after 24 hours. After 24 hours, U266 cells incubated with 100 nM GA were in both early and late stages of apoptosis; 17AEP and 17DMAG caused apoptosis of similar intensity to GA. It has been observed that GA and its derivatives cause caspase-3 activation. Analysis of the activity of AKT and MAP 42/44 kinases was performed by incubating U266 cells for 24 and 48 hours in100 nM of GA and its derivatives. After 24 hours incubation, no significant changes in protein expression were observed, while after 48 hours, the strongest changes were seen in AKT protein expression after incubation with GA and 17AEP-GA. In studies of the cell cycle, it was found that 100 nM 17AEP-GA and 17-DMAP-GA cause cell cycle abnormalities. We observed a nearly two-fold increase in U266 cells in the G1 phase and a simultaneous decrease in the percentage of cells in the G2/M phase, indicating that cells were halted in the G1 phase. In the case of the INA6 cells, proliferation was halted in both the G1 and G2/M phases.
Conclusions. GA and the analogues that we tested can inhibit myeloma cell growth by induction of apoptosis and blockage of cell cycle progression, and have an effect on the down-regulation of the MET receptor. The GA derivatives tested, despite their modifications still retain strong anticancer properties. Specifically, two analogues of GA, 17AEP-GA and 17DMAG due to their properties can be more effective and safer chemotherapeutic agents than 17AAG, which is currently used and described in literature.
Keywords: multiple myeloma, geldanamycin, 17DMAG, 17AEP-GA, 17DMAP-GA