The Luxembourg lab led by Prof. Marc Diederich has used a compound from a Mediterranean marine sponge to block the growth of cancer cells. Not only that, this molecule, called Iso-3, even enhances the effect of a cancer-fighting agent already in clinical trials, but to which many cancers are resistant. In a study published in the journal Oncotarget, the team explains the clues that led them to Iso-3 and how it works to decrease the ability of different kinds of cancer cells to multiply and form tumors.

Supported by Télévie Luxembourg

This research project was largely financed by the Télévie fundraiser, which supported both the project and the first author, Dr. Cristina Florean. On April 23rd, Luxembourg again showed solidarity by collecting funding for cancer research projects all over the country.

Reactivating tumor suppression

A common feature of cancer cells involves the mechanisms of epigenetics. Classical genetics might explore a given gene’s involvement in a disease, or identify the protein it produces. Epigenetics, on the other hand, has to do with modifications to the DNA’s larger structure. These don’t affect the sequence of the DNA, but do determine whether the gene is expressed or not. Adding a bunch of methyl groups, for instance (called hypermethylation) can turn a gene off. If its normal role is to suppress the formation of tumors, the development of cancer may become more likely.

Illustration of a methylated DNA molecule
Credit: Christoph Bock (Max Planck Institute for Informatics) - Own work, CC BY-SA 3.0, via Wikimedia Commons

So, what if you could remove that extra methylation: could you turn the tumor-blocking gene back on? That is what the LBMCC hoped to do with the sea sponge molecule, Iso-3. This approach is receiving a lot of attention in cancer research and two such demethylating agents have been developed, but their side effects in patients have spurred on the hunt for alternatives. The LBMCC turned to nature for inspiration and found their answer in the sea. Marine organisms boast a very rich chemical catalog and many of these substances have shown anti-cancer activity. In fact, a standard treatment for leukemia today is based on Ara-C, another compound derived from a sponge.

Iso-3 blocks cancer cell growth & tumor formation

After screening a large collection of natural compounds in the lab, the researchers identified an interesting candidate produced by the sea sponge Aplysina aerophoba. This was Iso-3, whose ability to reduce the addition of those methyl groups to DNA seemed to correspond with increased expression of tumor-blocking genes. The team observed a halt in the growth and replication of different types of leukemia cells, as well as changes indicative of autophagy—the self-dismantling process that damaged cells embark upon, usually leading to cell death. Other analyses confirmed the cancer tissue was, indeed, dying.

The Luxembourg group also checked for these benefits of Iso-3 treatment in zebrafish, to be sure the effect would be the same in a living organism. This was the case, with the fish developing fewer tumors with treatment. In contrast to the toxicity seen in cancer cells, and importantly for Iso-3’s potential therapeutic use, it had no harmful effect on blood cells from healthy human donors or on the animals’ embryonic development.

The marine sponge Aplysina aerophoba
Credit: Di Yoruno - Opera propria, CC BY-SA 3.0, via Wikimedia Commons

On the TRAIL of combination treatments

Another promising outcome of the LBMCC’s study involves TRAIL. This is a molecule that can trigger cell death, but many cancers are resistant to it and, so, get away with their uncontrolled growth. Pretreating cancer cells with Iso-3, the group found, sensitized them to the effects of TRAIL. This is important because, while TRAIL-based therapies are advancing in clinical trials, the resistance problem means non-toxic ways of increasing cancer cells’ sensitivity to them are badly needed.

Iso-3’s ability to bring aberrant cell growth to a halt could make it an excellent candidate for cancer drug development, in particular because compounds like this work against the out-of-control, pathological replication associated with disease. That means that they will specifically target cancer cells, unlike other forms of chemotherapy that blast all cells, even healthy ones, with toxic chemicals. Iso-3 could represent a non-toxic therapeutic alternative. Used in combination with existing cancer drugs, it could help lower the necessary doses of cytotoxic drugs and reduce their serious side effects for cancer patients.

See the original study here:

Discovery and characterization of Isofistularin-3, a marine brominated alkaloid, as a new DNA demethylating agent inducing cell cycle arrest and sensitization to TRAIL in cancer cells

Banner image credit:
"Aplysina aerophoba (Goldschwamm, Yellow tube sponge)", by Lars Behnke, via Flickr (CC BY-ND 2.0)