Rebecca Alexander, Ph.D.
Wake Forest University
Winston-Salem, North Carolina

Background:

Cell division is a complex process which involves many critical steps such as DNA replication and gene transcription.  Some anti-cancer drugs are cytotoxic (toxic to cells) agents which interfere with these steps.  As a result, they cause the cell to stop dividing, ultimately leading to cell death.  Unlike most healthy cells in our body, which do not divide under normal circumstances, cancer cells typically divide rapidly, thus are more susceptible to cytotoxic drugs.

Cisplatin is a cytotoxic anti-cancer drug that treats various types of cancer, including testicular cancer, small cell lung cancer, ovarian cancer, and lymphoma.  Research has revealed that this platinum-based compound causes DNA structural damage in the cells.  The damage makes it impossible for rapidly dividing cells - such as cancer cells - to duplicate their DNA.  Ultimately, the damaged DNA leads the cells to commit “suicide”, or apoptotic cell death.

Although cisplatin is effective in treating many types of cancer, especially testicular cancer, resistance often occurs after prolonged use, greatly decreasing its efficacy.  In addition, the side effects, such as nausea, vomitting, diarrhea, and loss of weight, are common, creating even more health concerns for cancer patients.  In order to overcome the acquired resistance and to reduce side effects, new platinum-based agents that function through different mechanisms are needed.

Project Director and Research:

NFCR Project Director Rebecca Alexander, Ph.D., in collaboration with Dr. Uli Bierbach at the Wake Forest University, is working against the clock to fullfill this challenging task.  Recently, a novel platinum-based compound, PT-ACRAMTU, has been synthesized in Dr. Bierbach’s laboratory.  This novel agent demonstrates potent anti-cancer effects in a broad range of solid tumor cell lines and may work differently from the currently available platinum-based chemotherapy agents.  This exciting discovery encouraged Dr. Alexander to elucidate how PT-ACRAMTU functions at the molecular level.  And it is not just for fun – study of the molecular mechanisms is critical for scientists to gain in-depth knowledge of novel compounds, and paves way for designing better drug candidates with improved biological activities and reduced side effects. 

Using multiple molecular and biochemical experimental approaches, Dr. Alexander and her research team revealed that PT-ACRAMTU kills cancer cells, at least partially, through interfering with gene expression, an essential process for cell division and cell function.  Further research demonstrated that the interference is achieved by reducing the binding of TATA-binding protein to DNA, which is a critical step to initiate gene expression.   Importantly, PT-ACRAMTU is likely to be the first platinum-based compound to kill cancer cells through this mechanism. This means that PT-ACRAMTU functions differently from cisplatin, and that it might be able to overcome tumor resistance to cisplatin.  Based on the knowledge gained from Dr. Alexander’s research, more compounds that target the same process as PT-ACRAMTU are to be designed and further evaluated for their anti-cancer effects.

Impact on Cancer Prevention, Treatment, or Cure:

The effort of Dr. Alexander’s team, in conjunction with Dr. Bierbach’s work, on elucidating how novel platinum-based chemical agents function at molecular level, provides invaluable information on understanding the mechanisms by which potential anti-cancer drugs function.  More importantly, the in-depth knowledge resulting from their work has established a platform that is essential for generating more rationally-designed, novel chemical compounds, with improved effects and lowered side effects for cancer treatment.