Abstract

Multiple Myeloma (MM) is the second most commonly diagnosed hematologic malignancy and still an incurable disease with dismal prognosis and average survival of 3 – 4 years. None of conventional therapies gives total cure or long survival, so it is urgently necessary to find new treatment strategies. Heat shock protein 90 (HSP90) is a potentially good therapeutic target, because it interacts with diverse and wide panel of client proteins that are important for proliferation and survival of tumor cells. Geldanamycin (GA) and its analog 17-allylaminogeldamycin (17AAG) are HSP90 inhibitors and were shown to block various tumor cells growth including MM cells. 17AAG has been already tested in clinical trials and showed some antitumor properties. There are, however, other inhibitors belonging to geldanamycin family such as: 17DMAG, 17DMAP and 17AEP which have not been tested against multiple myeloma cell lines and primary samples.

In this study we looked at the influence of GA and its analogs on proliferation and apoptosis of MM cells. We found that GA at 100 nM concentration inhibited growth of MM cells by 80%, 17AEP by 75%, 17DMAG and 17DMAP by 70% and 17AAG by 30%. Primary MM cells were more resistant and at 100 nM concentration we observed 30% inhibition with GA and 17DMAG. At the same time 17AAG did not effectively inhibit proliferation of primary MM cells.

We also analyzed influence of 100 nM concentration of GA and analogs on the apoptosis of MM primary cells and cell lines after 6 h and 24 h of incubation. Percentage of Anexin V and propidium iodine double positive geldanamycines treated primary MM cells was similar to the control after 6 h but change after 24 h. In comparison to control, number of apoptotic cells increased by: 175% for 17DMAG, 140% for GA, 80% for 17DMAP and 17AEP, no changes in number of apoptotic cells were observed for 17AAG. Similar observation was made for MM cell lines and increase in number of Anexin V positive cells was noticed. Again, percentage of Anexin V positive cells did not increase after treatment with 17AAG and remained at the control level. We also observed, similarly to others, substantial block in G1 and G2/M phase of cell cycle in cells treated with GA and its analogs. In conclusion, besides to 17AAG other HSP90 inhibitors could be considered as potential therapeutics for treatment of MM. Particularly, based on our data, we suggest that 17DMAG and 17AEP are new HSP90 inhibitors that should be tested in a clinic because they exert strong MM cells growth inhibition.

Disclosure: No relevant conflicts of interest to declare.

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