International journal of clinical and experimental medicine

Halichondrin B amide acts as tubulin binding agent to exhibit anti-tumor efficacy in hematologic cancers.

PMID 26770630


Since microtubule dynamics play an indispensable role in cell division, cell motility, cellular transport, cell polarity and cell signalling, the microtubule appears as a highly attractive target for anticancer drug design. The present study demonstrates the role of halichondrin B amide (HCBA), an analog of halichondrin Bas an antitumor agent, its mechanism of action and pharmacokinetics. The results revealed that HCBA effectively inhibitscell growth in a variety of tumor types in vitro. The HCT116 DPC4 (-/-) colon cancer cell line was the most sensitive with an IC50 of 2.02 μM, compared to 3.78 μM in the parental HCT116. It also effectively reduced tumor growth in SCID mice human tumor xenografts of MV-4-11 acute myeloid leukemia, MM.1S multiple myeloma and DU-145 prostate cancer. HCBA caused accumulation of H69S, MM.1S, U266 and 8226/S cells in G2/M-phase after 24 h. There was a significant increase in the positive histone H3 cells from a baseline value of 4.38 to 53.45% in 8226/S cells and from 4.32 to 43.83% in MM.1S cells on treatment with HCBA. The results from pharmacokinetic studies demonstrated relatively high oral bioavailability of 83% with distribution in both plasma and bone marrow. In non-tumor bearing SCID mice injected with a single acute lethal dose of HCBA no myelosuppression was observed. Flow cytometry analysis showed cell cycle arrest in metaphase. It also caused inhibition of tubulin polymerization. Thus, HCBA appears to be a potent agent to arrest cell cyclin the metaphase and inhibit tubulin polymerization. Compared to other existing microtubule destabilizing agents HCBA has good oral bioavailability and lacks MDR cross-resistance acute myelosuppression.