From the Fruit Fly to You: A Bench to Bedside StorY Continued:

“It was a bit of a leap to think that the SDs in the fly or in the soy might be the active agent that could protect against colon cancer, but that’s the kind of leap that an oncologist studying developmental biology would make, because you’re always thinking about everything you study from a cancer perspective,” says Dr. Saba, who actually started her career as a clinical researcher on the cancer ward.

“You’re always thinking about everything you study from a cancer perspective.”
It was a leap that paid off in spades, however, beginning with the determination that SDs from both the mutant fruit fly and soy could induce cancer cell death.

“Both types of SDs inhibited the growth of a number of different colon cancer cell lines, but not non-cancerous cell lines, which is the type of specificity you hope to find,” says Dr. Saba of the first step in the series of experiments.

Dr. Saba and her colleagues next determined that the SD-treated cancer cells were actually dying through two different mechanisms of cell death, the more common form of apoptosis, as well as the less common, autophagy.

“Apoptosis usually occurs in response to stress, such as chemotherapy, for example. It’s a way in which the cells break down all their components and essentially commit suicide,” says Dr. Saba.

During autophagy, however, the cell dies by an entirely different method.

As Dr, Saba explains, “Autophagy literally means "eating oneself up", and that’s exactly what the cells do. It’s an ancient process that cells undertake when they are deprived of nutrients."

To prolong the amount of time the cell can survive until nutrients are restored, the cells start engulfing internal parts, breaking them down to the basic components of life such as amino acids and sugars, and reusing them for energy and to rebuild necessary proteins until the nutrient supply is restored. If that does not happen, autophagy continues until the cell dies.

That SDs induced both autophagy and apoptosis in cancer cells suggested that SDs were able to interfere with the Akt pathway, which suppresses both apoptosis and autophagy.

"The Akt pathway is probably the most important cancer-associated pathway that has been discovered to date," Dr. Saba explains. "It’s normally activated to stimulate growth and metabolism by appropriate growth factors at appropriate times. In cancer cells, though, the pathway gets uncoupled from whatever the outside world is telling it, and gets stuck in the "on" position, activating cell growth and suppressing cell death in a very unhealthy way.”

Further studies revealed that SDs were in fact interfering with the Akt pathway by preventing a key component of the pathway from becoming activated, suggesting that the SDs, whether from the fruit fly or from soy, could be an effective therapeutic agent against colon cancer. This hypothesis was subsequently confirmed in a mouse model of colon cancer treated with SDs.

“The SDs were very effective in mice that had already developed tumors, even though we were only treating them for a brief amount of time," says Dr. Saba.
“There was virtually no toxicity associated with the treatments, and yet these mice had many fewer tumors than mice that were not fed SDs.”
Thus, with one fell swoop of a tiny little mutant fruit fly, Dr. Saba’s group both identified a new class of therapeutic agents that effectively prevents colon cancer cell survival in the Petri dish, and reduces colon cancer tumor size and number in a model of active colon cancer.

“Sphingolipids have great potential as modulators of cell growth and death pathways,” says Dr. Saba. “I think in this particular case, I would be comfortable recommending soy products as a preventative change in the diet that could protect against cancer. The more that soy is studied, the more of these protective agents are found, so it’s a very healthy diet choice.

As the oncologist-turned-biologist says, “I eat a lot of tofu.”

Future studies are already underway to identify the best method of delivering SDs – as a drug versus a nutritional supplement for example – as well as to confirm the lack of overall toxicity when the compounds are used for extended time periods and possibly in combination with other agents. Dr. Saba has already received two grants to take the research to the next level, and hopes in addition to be able to test whether or not SDs might be equally as effective in the blood stream as in the gut, which could have implications for other types of cancer as well.

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