New anticancer molecule promises improved therapy

Chemotherapy without side effects, or the risk of relapse, could soon be possible.

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@2016 KAIMRC

Scientists have developed an anti-cancer agent that, in lower doses, can kill cancer cells and spare healthy ones — presenting a favourable therapeutic scenario in which relapse is unlikely.   

Cancer accelerates cell division and disrupts their ability to become more specialized; a process called differentiation. An ideal chemotherapeutic drug will stop proliferation of cancer cells and promote cell differentiation.  

Chemotherapy is a widely used option, but drug resistance is common and the treatment can be toxic to normal tissues. Pharmaceutical chemists are trying to find potent, resistance-free and safe drugs to treat cancer. 

This is what G-11, a new compound proposed by Ayman Saleh, lead author of two new papers on the subject 1,2, is promising.   

The G11 molecule targets cells that develop a mutation in the FLT3 receptor, which is important for cell propagation and proliferation. The mutant is most common in acute myeloid leukemia1, which represents approximately 90% of all acute leukaemias in adults. Chemotherapy is initially effective, but relapse is common and long-term survival rates are below 20%.  

“If the cancer is smart, once [a chemotherapeutic] drug targets a pathway, the cancer will find a new way to propagate. A few resistant cells will be left behind, they will flourish and become more vicious,” says molecular biologist Saleh from King Saud bin Abdulaziz University for Health Sciences. “Our drug, however, can target both existing and potential pathways, preventing relapse.”  

“What we’re doing here is developing a superior weapon; an air fighter that would minimize collateral damage by diving inside an enemy cell and killing its organelles,” he says.  

Organelles are the complex cell structures enclosed within lipid membranes inside a cell. These membranes carry the genetic material and nucleolus. Their fuel comes from the mitochondria, another organelle that functions as the cell’s powerhouse, providing energy for all cellular activities, including growth and division.  

G-11 precisely targets the mutated receptor FLT3 in a cancer cell, shutting down its power supply.  

By disrupting mitochondrial functions, Saleh’s anti-cancer molecule destroys a cell from the inside while keeping the outer shell of the cell intact. How the cell dies makes all the difference.  

In necrosis, a form of premature cell death, the cell bursts, contaminating healthy cells with its contents and triggering an aggressive immune response, ultimately leading to organ damage. Many available cancer drugs can cause cell necrosis. 

By keeping the outer membrane of the cell unscathed in death, G-11 causes apoptosis2, which is “the dignified way to die” from a cellular perspective, says Saleh. Apoptosis doesn’t have side effects.  

G-11 not only inhibits FLT3 expression, but also promotes cell differentiation of blood cancer cells into mature cells1 `– cells that are no longer able to divide.

The compound was checked against a broad spectrum of cancers and proved effective1. It was more toxic to cancer cells than normal cells. Killing normal cells would require triple the G-11 dose that kills cancer cells. 

Saleh tested the compound on acute myeloid leukaemia blood samples. The promising results are “encouraging us to start the next step, which is investigating the compound in a leukaemia animal model to potentially qualify the compound to be tested on humans,” he says.

References

  1. Saleh, A. M. et al. Novel anticancer compound [trifluoromethyl-substituted pyrazole N-nucleoside] inhibits FLT3 activity to induce differentiation in acutenmyeloid leukemia cells. Cancer Letters. (2016) | article
  2. Saleh, A. M. et al. Cytotoxic activity of the novel heterocyclic compound G-11 is primarily mediated through intrinsic apoptotic pathway. Apoptosis (2016) | article

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