A Small Molecule Drug that Selectively Induces Apoptosis in Cancer Cells

This cancer research is interesting for the strong resemblance it bears to current senolytic strategies to destroy senescent cells by forcing them into the programmed cell death process of apoptosis: these cells are primed for that fate, but fail to reach it on their own. The therapies used affect normal cells as well as the targeted senescent cells, but cause little impact in the healthy cells that should be spared. This same type of approach is here applied to cancerous cells, using a close relative of the pro-apoptosis targets employed for senescent cells. Considered at the high level, this makes an interesting counterpoint to the trend towards the development of precision targeting in cancer research: any method of killing cells is useful if it can be restrained to only the cells that should be killed. Therein lies the challenge, of course.

In principle it seems possible to produce a therapy that can be globally applied throughout the body but only does harm to cancerous cells - though in practice such selectivity is a sliding scale, and nothing is perfect. Causing less harm to the patient than the current standard of chemotherapy is a low bar, but conversely the effectiveness of this first attempt seems marginal. It is only slowing down cancer a little rather than fixing the problem. Still, it is only the starting point for a whole new area of exploration.

Scientists have discovered the first compound that directly makes cancer cells commit suicide while sparing healthy cells. The new treatment approach was directed against acute myeloid leukemia (AML) cells but may also have potential for attacking other types of cancers. The newly discovered compound combats cancer by triggering apoptosis - an important process that rids the body of unwanted or malfunctioning cells. Apoptosis trims excess tissue during embryonic development, for example, and some chemotherapy drugs indirectly induce apoptosis by damaging DNA in cancer cells.

Apoptosis occurs when BAX - the "executioner protein" in cells - is activated by "pro-apoptotic" proteins in the cell. Once activated, BAX molecules home in on and punch lethal holes in mitochondria, the parts of cells that produce energy. But all too often, cancer cells manage to prevent BAX from killing them. They ensure their survival by producing copious amounts of "anti-apoptotic" proteins that suppress BAX and the proteins that activate it. "Our novel compound revives suppressed BAX molecules in cancer cells by binding with high affinity to BAX's activation site. BAX can then swing into action, killing cancer cells while leaving healthy cells unscathed."

Researchers first described the structure and shape of BAX's activation site in 2008, and have since looked for small molecules that can activate BAX strongly enough to overcome cancer cells' resistance to apoptosis. The team initially used computers to screen more than one million compounds to reveal those with BAX-binding potential. The most promising 500 compounds were then evaluated in the laboratory. A compound dubbed BTSA1 (short for BAX Trigger Site Activator 1) proved to be the most potent BAX activator, causing rapid and extensive apoptosis when added to several different human AML cell lines. The researchers next tested BTSA1 in blood samples from patients with high-risk AML. Strikingly, BTSA1 induced apoptosis in the patients' AML cells but did not affect patients' healthy blood-forming stem cells.

Finally, the researchers generated animal models of AML by grafting human AML cells into mice. BTSA1 was given to half the AML mice while the other half served as controls. On average, the BTSA1-treated mice survived significantly longer (55 days) than the control mice (40 days), with 43 percent of BTSA1-treated AML mice alive after 60 days and showing no signs of AML. Importantly, the mice treated with BTSA1 showed no evidence of toxicity.

Link: http://www.einstein.yu.edu/news/releases/1272/novel-treatment-causes-cancer-to-self-destruct-without-affecting-healthy-cells/


This BAX - BSTA1 approach is nice, but at this point in the game we actually have better ways to approach AML. Actually we already know exactly what the deeper problem with AML mitochondria seems to be.

The real question is why do AML blasts, in contrast to many typical cancers where the Warburg effect reigns, rely on oxidative phosphorylation for survival. In particular why do they have so many mitochondria?

The answer was published in 'Blood' back in July, and the story was re-run last week as the cover feature:
'Bone Marrow Mesenchymal Stromal Cells Transfer Their Mitochondria to Acute Myeloid Leukaemia Blasts to Support Their Proliferation and Survival'

The papers show that the mitochondria responsible for transforming malignant AML blasts are supplied by bone marrow stromal cells (BMSCs). This heterogenous population of local stromal cells includes precursors of endothelial cells, osteoclasts, osteoblasts, adipocytes, and fibroblasts. The way the AML blasts get the mitochondria is by extending tunneling nanotubes to the BMSCs. The way that blasts make the nanotubes is by generating superoxide radical with NADPH oxidase. The authors said the tunneling nanotubes are 'AML-derived' but when I pressed them on this they failed to explain why they make this claim.

Now I figured it should be possible to investigate even further where the mitos are coming from. A significant problem with many common chemotherapies is they take a huge toll on the hematopoietic system that generates new blood cells. It turns out that the drugs destroy the adrenergic nerve endings that contact stem cells niches in the bone marrow to promote their survival. Without these sympathetic nerves, proliferation and differentiation of hemotpoietic cells grinds to a halt, see;

Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. https://www.nature.com/nm/journal/v19/n6/full/nm.3155.html

I just related how sympathetic nerves trophically support the marrow stem cell pool, and how the marrow cells support AML blasts. What do we get when when put these two observations together? One exemplary possibility we can infer is a multi-hop mitochondrial transfer circuit from nerve to marrow cell to AML blast.

Posted by: john hewitt at October 10th, 2017 7:17 AM

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