Skip to main content

New Tubulin Polymerization Inhibitor Derived from Thalidomide: Implications for Anti-Myeloma Therapy

Buy Article:

$63.00 plus tax (Refund Policy)

Abstract:

Despite the conventional and high-dose chemotherapy with hematopoietic stem cell transplantation, multiple myeloma eventually relapses, resulting in an incurable hematological malignancy. Therefore, novel therapeutic approaches in clinical settings are desired. Recently, thalidomide was introduced for the treatment of myeloma, and many clinical trials have since confirmed its efficacy in patients with relapsed/refractory or newly diagnosed multiple myeloma. Multiple mechanisms have been proposed to explain thalidomide's antimyeloma activity. However, the precise mechanism underlying this activity remains unclear, because thalidomide rapidly undergoes spontaneous, nonenzymatic, hydrolytic cleavage to numerous metabolites in vivo. To elucidate the exact anti-myeloma mechanism of thalidomide in vivo, we have performed structural development studies of thalidomide, and obtained various analogs with specific molecular properties. Among these derivatives, we found that a new thalidomide analog, 2-(2,6-diisopropylphenyl)-5-hydroxy-1H-isoindole- 1,3-dione (5HPP-33), has the most potent anti-myeloma effect with tubulin polymerization inhibiting activity. 5HPP-33 directly inhibited the growth and survival of various myeloma cells in a dose-dependent manner with IC50 of 1-10 μM. In contrast, thalidomide itself did not inhibit RPMI8226 cell growth. A tubulin polymerization assay using microtubule protein from porcine brain revealed that 5HPP-33 had potent tubulin polymerization inhibiting activity with IC50 of 8.1 μM, comparable to that of rhizoxin, a known tubulin polymerization inhibitor. Moreover, its activity was more potent than that of a known thalidomide metabolite, 5-hydroxythalidomide. Our data suggest that 5HPP-33 is a promising candidate as a therapeutic agent for multiple myeloma. In addition, the results suggest that thalidomide's tubulin polymerization inhibiting activity might be the mechanism underlying the induction of apoptosis in myeloma cells.

Keywords: 5HPP-33; Thalidomide; apoptosis; metabolite; multiple myeloma; structural development; tubulin polymerization inhibitor

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986708783955473

Affiliations: Division of Hematology, Department of Internal Medicine, Saitama Medical Center, Saitama Medical University, 1981 Tsujido-machi, Kamoda, Kawagoe, Saitama 350-8550, Japan.

Publication date: April 1, 2008

More about this publication?
  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
ben/cmc/2008/00000015/00000008/art00003
dcterms_title,dcterms_description,pub_keyword
6
5
20
40
5

Access Key

Free Content
Free content
New Content
New content
Open Access Content
Open access content
Subscribed Content
Subscribed content
Free Trial Content
Free trial content
Cookie Policy
X
Cookie Policy
ingentaconnect website makes use of cookies so as to keep track of data that you have filled in. I am Happy with this Find out more