PX-12, Inhibitor of Trx-1 as Anti-cancer Agent?

PX-12, Irreversible inhibitor of Trx-1
Potential health benefits on colon, renal, lung, and gastric cancers and research
finds 2007

What is Thioredoxin-1 (Trx-1)?
Thioredoxin-1 (Trx-1) is a small redox protein that is
over-expressed in many human tumors. Thioredoxin-1
(Trx-1) is secreted by tumor cells and is present at increased
levels in the plasma of cancer patients. [2] Increased
thioredoxin levels in cancer cells have been linked to the
aggressive proliferation of solid tumors, including colon, lung,
and gastric cancers. [1]

In 2002, Powis G and his group from University of Arizona
reported that the expression of CYP1B1 mRNA and protein is
increased by thioredoxin-1 (Trx-1) transfection of MCF-7
human breast cancer cells and decreased by a redox inactive
mutant Trx-1. [3]

CYP1B1 expression is elevated in a wide range of human
cancers but is not found in corresponding normal tissue. It is
also a cytochrome mediates one of the two major pathways
of estrogen metabolism. Cytochrome CYP1A1 mediates the
other pathway of estrogen metabolism. Oxidative metabolites
of estrogen have been proposed to play an important role in
the development of some human cancers. [3]

Thioredoxin-1 (Trx-1) is a small redox protein that is
over-expressed in a number of human cancers. Trx-1 is
involved in the constitutive expression of CYP1B1 and is
required for the induction of CYP1B1 and CYP1A1. [3]

The Trx-1 inhibitor PX-12 inhibits CYP1B1 gene expression.
[3]

How does PX-12 work against the cancers in test-tubes,
in animals and in patients?
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor
that plays a critical role in tumor growth by increasing
resistance to apoptosis and the production of angiogenic
factors such as vascular endothelial growth factor (VEGF).
While, the redox protein thioredoxin-1 (Trx-1), which is
found at high levels in many human cancers, increases both
aerobic and hypoxia-induced HIF-1alpha protein in cells
leading to increased expression of HIF-regulated genes. [4]

Powis G and his group found that treatment of MCF-7 human
breast cancer and HT-29 human colon carcinoma cells with
PX-12 and pleurotin prevented the hypoxia (1%
oxygen)-induced increase in HIF-1alpha protein. This
combination also decreased HIF-1-trans-activating activity,
VEGF formation, and inducible nitric oxide synthase under
hypoxic conditions. [4] PX-12 and pleurotin also decreased
HIF-1alpha protein levels and HIF-1 trans-activation in RCC4
renal cell carcinoma cells. [4]

In 2004, Powis G and co-workers found that PX-12 caused a
rapid 63% decrease in the average tumor blood vessel
permeability in a tumor xeno-graft of mice within 2 hours of
administration. And, they observed a decrease in tumor,
VEGF levels and a rapid decline of Trx-1 levels after the 24
hour of PX-12 administration. [5]

Last year, Powis G and his co-workers measured plasma
Thioredoxin-1 (Trx-1) from patients treated with PX-12
during a phase I study. Before the treatment, the mean
plasma thioredoxin-1 (Trx-1) level was 182.0 ng/mL while
that for healthy volunteers in the study was 27.1 ng/mL. [2]

As expected, they observed that PX-12 treatment
significantly lowered plasma Thioredoxin-1 and vascular
endothelial growth factor (VEGF) in cancer patients. They also
noticed the correlations between the high-plasma vascular
endothelial growth factor (VEGF) levels and decreased patient
survival. [2]

Well, it is an exciting beginning, but, we still need to see the
data from Phase III. Currently, Biomira Inc. starts a Phase II
clinical trail of PX-12 in patients with advanced pancreatic
cancer. [1]

This article is for reference only. Consult with your doctor for medical advice.
ALL RIGHTS RESERVED ZHION 2007.

[1] Phase II clinical trial of Biomira's PX-12 in patients with advanced
pancreatic cancer now open for patient enrollment Tuesday PRNewswire
January 2, 2007 8:00 am [2] Baker AF, et al, The antitumor thioredoxin-1
inhibitor PX-12 (1-methylpropyl 2-imidazolyl disulfide) decreases
thioredoxin-1 and VEGF levels in cancer patient plasma. J Lab Clin Med. 2006
Feb;147(2):83-90. [3] Husbeck B, Powis G. The redox protein thioredoxin-1
regulates the constitutive and inducible expression of the estrogen
metabolizing cytochromes P450 1B1 and 1A1 in MCF-7 human breast cancer
cells. Carcinogenesis. 2002 Oct;23(10):1625-30. [4] Welsh SJ, et al, The
thioredoxin redox inhibitors 1-methylpropyl 2-imidazolyl disulfide and
pleurotin inhibit hypoxia-induced factor 1alpha and vascular endothelial growth
factor formation. Mol Cancer Ther. 2003 Mar;2(3):235-43. [5] Jordan BF, et al,
The thioredoxin-1 inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12)
decreases vascular permeability in tumor xenografts monitored by dynamic
contrast enhanced magnetic resonance imaging. Clin Cancer Res. 2005 Jan
15;11(2 Pt 1):529-36.

What is PX-12?
PX-12 (Biomira Inc.) an irreversible inhibitor of Thioredoxin-1 (Trx-1) currently in clinical
development as an antitumor agent. [2]