A team of UT Arlington
researchers has identified two ruthenium-based complexes they believe could
pave the way for treatments that control cancer cell growth more effectively
and are less toxic for patients than current chemotherapies.
Fred MacDonnell, professor of chemistry and biochemistry at The
University of Texas at Arlington, has been researching a new generation of
metal-based antitumor agents along with a team from the City of Hope
Comprehensive Center Center in Duarte, Calif. Their aim is to find new therapies
to complement widely used platinum-based therapies, such as cisplatin. Cisplatin is one of the most widely used
anti-cancer drugs and shows remarkable effectiveness against some cancers,
however it does not work on all cancers and can have severe side effects.
In a study published in the May
edition of Molecular Cancer Therapeutics,
the team describes two newly developed ruthenium polypyridyl complexes, or
RPCs, that yielded results comparable to cisplatin against human non-small cell
lung cancer cells in pre-clinical lab tests.
A graphic from MacDonnell's paper shows the growth of a control tumor
compared to the growth of tumors treated with ruthenium-based complexes
developed in the lab.
Unlike cisplatin, the RPCs were
generally cleared from the body unchanged, without noticeable effects on
metabolism or kidney function. In lab tests, healthy cells could
withstand almost 10 times as much exposure to the team’s ruthenium complexes as
the cancer cells.
The study also found that the
RPCs seemed to target cells in hypoxic states. Hypoxia, or low oxygen, is a
signature of tumor cells.
“Cancer drugs on the market now generally are less effective under
hypoxic conditions or insensitive to the oxygen concentration,” MacDonnell
said. “Since many tumor cells are under hypoxic stress and most normal cells
are not, having something that becomes even more effective under hypoxia could
have some real benefit to the patient.”
The effectiveness of the RPCs tested seems to be associated with a particular
portion of their structure. This portion, known as “tatpp” is redox-active,
which means it is reduced when bound to DNA in the normal cellular
environment. MacDonnell’s team believe
that this reduction step in the DNA bound compound sets in motion a biological
process that triggers apoptosis, also known as programmed cell death, in cancer
cells. Under hypoxic conditions, this
reduction is more prevalent, leading to greater cell death in those cells.
activated under low-oxygen conditions makes these unique complexes excellent
candidates for use on some of the most difficult to treat tumors," said
Dr. Sanjay Awasthi, professor of medical oncology and therapeutics research at
City of Hope. "Now that we have demonstrated the role of the tatpp ligand
in these biological processes, our team can continue toward the goal of using
ruthenium-based complexes to enhance current treatments."
MacDonnell said the ruthenium complexes’ increased effectiveness
against malignant cells could be because the complexes can more easily enter
cancer cells, which tend to be more metabolically active than normal cells.
That hypothesis, however, is something the team will explore with further research.
The paper, called “Regression of lung cancer by hypoxia-sensitizing
ruthenium polypridyl complexes,” is available online at: http://mct.aacrjournals.org/content/12/5/643.short?rss=1&co=f000000009816s-1158206718. Grants from the National Institutes of
Health’s National Cancer Institute and the Robert A. Welch Foundation supported
Besides MacDonnell and Awasthi, co-authors are: Abhishek Yadav,
Thamara Janaratne, Adam S. Dayoub and Arthi Krishnan, of the UT Arlington
chemistry/biochemistry department; Doyle H. Hawkins, of the UT Arlington math
department; and Sharad S. Singhal and Sushma Yadav, of the City of Hope
Comprehensive Cancer Center.
MacDonnell’s work is representative of the
scientific advances under way at The University of Texas at Arlington, a
comprehensive research institution of more than 33,200 students and more than
2,200 faculty members in the heart of North Texas. Visit www.uta.edu to learn more.