New Molecule Kills Resistant Cancer Cells in Acute Myeloid Leukemia

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Highlights:

• Scientists have reported the discovery of BTSA1 which can effectively induce apoptosis (cell death) in cell lines of acute myeloid leukemia while protecting healthy cells
• BTSA1 is a pharmacological BAX activator with high binding capacity that can act as a pro-apoptosis regulator to kill cancer cells
• BTSA1 is believed to revive suppressed BAX molecules in cancer cells thereby promoting BAX action in killing cancer cells.

New Molecule Kills Resistant Cancer Cells in Acute Myeloid Leukemia

Scientists at the Department of Medicine, Albert Einstein College of Medicine, NY have discovered a new molecule which kills resistant cancer cells in acute myeloid leukemia. The scientists reported the discovery of BTSA1 which can effectively induce apoptosis (cell death) in cell lines of acute myeloid leukemia while protecting healthy cells. BTSA1 (BAX trigger site activator) is a pharmacological BAX activator with high binding capacity.

The novel study was reported in the journal Cancer Cell.

‘Scientists discover that a molecule called BTSA1 can kill resistant cancer cells through apoptosis in acute myeloid leukemia but spare healthy cells. This molecule may have potential for attacking other types of cancers as well.’

BAX belongs to the Bcl-2 gene family and can act as a pro-apoptosis regulator to kill cancer cells. During this process, BAX molecules target the mitochondria in cells. Targeting the mitochondria in cells can cut off the cell's energy source thereby killing such cells. AML cells often evade the apoptosis action of BAX cells by producing "anti-apoptotic" proteins which suppress its actions.

The new compound BTSA1 can revive the suppressed BAX molecules in cancer cells as it has a high binding affinity to BAX activation sites. BAX can then restart its apoptotic activity and kill the cancer cells.

An estimated 351, 965 AML cases occurred in 2012 globally. Less than 30% survive beyond 5 years. AML is an aggressive cancer and novel treatments are required to target this type of cancer.

Discovery of the BTSA1 Compound

Dr. Evripidis Gavathiotis first described the structure and shape of a BAX activation site in a 2008 paper in Nature. Dr. Gavathiotis has been looking for small molecules which can activate BAX in its apoptotic activity. His team screened more than 1 million compounds to look for molecules with high binding affinity. Of these, 500 candidate molecules (some newly synthesized in their lab) were evaluated for binding efficiency.

BTSA1 proved to be the most effective and efficient molecule in binding with BAX site and activating apoptotic activity in leukemia cell lines and patient samples. While it activated BAX sites for cancer cell death, it did not harm the healthy cells. In mouse models, mice treated with BTSA1 survived longer (55 days) compared to the control mice (40 days). Of these, 43 percent of BTSA1-treated mice were alive even after 60 days with no signs and symptoms of recurring AML. The study evaluated both efficacy and toxicity and the BTSA1-treated mice showed no signs of toxicity while staying free from AML symptoms.

What is Acute Myeloid Leukemia?

Acute myeloid leukemia (AML) is a type of leukemia which develops in cells that go onto becoming white blood cells (WBCs). In some cases, AML can also develop in other types of blood-forming cells. It usually begins in the bone marrow (origin of all types of blood cells) and quickly spreads to other parts of the body like lymph nodes, central nervous system, liver and spleen. It is called "acute" because the spread is rapid. Without immediate treatment, an affected person will not live beyond a few months.

AML symptoms are hard to differentiate from other diseases; hence diagnosis can often be delayed. Signs and symptoms include:

• weight loss
• fatigue
• fever
• low appetite
• general malaise

Treatment for AML includes chemotherapy along with other targeted drug therapies. In some cases, bone marrow transplant or stem cell therapy may be an option.

In the future, Dr. Gavathiotis and his team have plans to see whether BTSA1 will show similar effectiveness when tested on animal models of other types of cancer.

References:

1. Denis E. Reyna, Thomas P. Garner, Andrea Lopez, Felix Kopp, Gaurav S. Choudhary, Ashwin Sridharan, Swathi-Rao Narayanagari, Kelly Mitchell, Baoxia Dong, Boris A. Bartholdy, Loren D. Walensky, Amit Verma, Ulrich Steidl, Evripidis Gavathiotis. (2017). "Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia". Cancer Cell, 32(4), pp.490-505.e10.DOI: http://dx.doi.org/10.1016/j.ccell.2017.09.001
2. Novel Treatment Causes Cancer to Self-Destruct Without Affecting Healthy Cells - (http://www.einstein.yu.edu/news/releases/1272/novel-treatment-causes-cancer-to-self-destruct-without-affecting-healthy-cells/)
3. What Is Acute Myeloid Leukemia? - (https:www.cancer.org/cancer/acute-myeloid-leukemia/about/what-is-aml.html)
4. Acute Myelogenous Leukemia And Acute promyelocytic Leukemia - (http://www.who.int/selection_medicines/committees/expert/20/applications/AML_APL.pdf)

Source: Medindia

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