Pyroxamide (nsc696085) - a potential anti-cancer hdac inhibitor

 

INTRODUCTION:

Histone acetylation and deacetylation status decides the regulation of gene expression and affects the genes involved in cell survival or apoptotic pathways. This is the reason that HDAC inhibitors are potent cytotoxic compounds and are seen as a treatment therapy for many transformed cells [1-2] as they disrupt chromatic structure of tumor cells with improved specificity [3].

PYROXAMIDE (NSC696085): THE ORIGIN

Pyroxamide is a small molecule HDAC inhibitor and comes usually in the form of its amine, 4-(Fingolimod)-5-hydroxy-6-methyl-3-pyridinemethanol dihydrochloride. Its rational design to lend it improved specificity against tumor cells made it an attractive new target for anti-cancer studies [4]. The first successful study involving Pyroxamide (NSC696085) showed specific apoptosis of murine erythroleukemia (MEL) cells [5].

RESEARCH STUDIES:

Pyroxamide showed promise in the treatment of kidney diseases in diabetic condition and its early progression was significantly suppressed upon Pyroxamide treatment in the murine model of Streptozotocin induced diabetes [6]. A clinical trial in 2002 by National Cancer Institute was conducted to check its efficacy in patients with advanced stages of cancer in a phase I study. There are a number of patents filed for the use of Pyroxamide in the treatment of neurodegenerative diseases. It has been used as a part of treatment regimen against gynecologic cancer [7] for treating cervical and ovarian cancer.

PYROXAMIDE (NSC696085) – A HISTONE-DEACETYLATING ANTI-CANCER AGENT:

From a group of many HDAC inhibitors, Pyroxamide showed a marked ability to kill different kinds of tumor cells in culture [3] which was confirmed by its ability to arrest leukemia cell cycle to facilitate apoptosis in murine model of erythroleukemia (MEL) cells [5]. Pyrodoxamide showed potent efficiency in killing B-cell precursor childhood acute lymphoblastic leukemia [8-9] cells in culture system. A very recent study extended this work in the early stages of adult acute lymphoblastic leukemia (ALL) in human patients [10] and reported an enhanced overall survival.

Pyroxamide has been used for in vitro and in vivo studies against human Rhabdomyosarcoma and it showed a dosage-dependent decrease in rhabdomyosarcoma (RMS) cells viability [11]. A recent study showed promise for various HDAC inhibitors in treatment of Cervical cancer, and Pyroxamide is considered to be included in the trials [12].
CONCLUSION:

A study on the characterization of various member of HDAC inhibitors family showed their mechanism of action that included not only suppression of cell proliferation, but caused massive changes at the level of gene regulation to promote cancer cell apoptosis [13]. As there are reports of successful use of other HDAC inhibitors like SAHA [14] in cell culture and of TSA in human carcinoma cells [15], Pyroxamine is surely going to get tested in these malignancies.

REFERENCES:

1.             Marks, P.A.e.a., Histone deacetylases and cancer: causes and therapies. Nature Reviews Cancer, 2001. 1: p. 194-202.
2.             Marks, P.e.a., Histone deacetylase inhibitors as new cancer drugs. Current Opinion in Oncology, 2001. 13(6): p. 477-483.
3.             Remiszewski, S.W., Recent advances in the discovery of small molecule histone deacetylase inhibitors. Curr Opin Drug Discov Devel., 2002. 5(4): p. 487-99.