Melanoma: New, More Effective Drug Steps Closer

Skin cancer is the most pervasive form of cancer in the United States. Melanoma accounts for the vast majority of skin cancer deaths; it is estimated that every hour, one U.S. individual dies from it. The condition has been referred to as the “deadliest form of skin cancer.”

The scientists were led by Dr. Arun Sharma, an associate professor of pharmacology, and Dr. Shantu Amin, a professor of pharmacology, both of Penn State College of Medicine in Hershey.

People with melanoma are currently being prescribed drugs that are either not well tolerated, or to which the tumors become resistant within 6 to 7 months. But as the researchers explain, their compound may succeed where other drugs have failed.

A ‘fragment-based drug design’

The compound is called napthalamide-isoselenocyanate (NISC-6) and the scientists used different fragments from their previous research to form it. Namely, they used an isoselenocyanate moiety from a drug they had previously designed and tested.

They had developed this moiety, or molecule fragment, from isothiocyanates, which are chemicals that can be naturally found in cruciferous vegetables such as broccoli, Brussels sprouts, cauliflower, kale, and cabbage.

These plants are thought to have anticancer properties. However, as the researchers note, while it is advisable to consume these vegetables to prevent cancer, the chemical compound on its own may not be enough to work therapeutically.

So, the scientists combined this isoselenocyanate moiety with another compound referred to as napthalamide moiety of mitonafide.

This latter substance is a so-called topoisomerase II alpha inhibitor. Typically, these inhibitors are used to stop DNA replication in cancer, and they have been used as anticarcinogenic drugs.

Mitonafide has been shown to work against tumors in clinical trials, but toxicity levels were too high.

NISC-6 inhibits tumors by 69 percent

The researchers made small variations to their new compound and tested its effectiveness, and they finally reached a design of the drug that did not increase toxicity levels.

In a mouse model, the compound reduced tumors by 69 percent and effectively caused melanoma cells to die. “We designed it for easy elimination from the body, so, consequently, toxicity should be reduced,” says Prof. Sharma.

An additional way in which the new drug may be better than currently available medicine, the researchers note, is that it targets different kinds of melanoma cells, thus overcoming the cancer’s resistance to drugs.

Namely, the NISC-6 compound attacks both “BRAF mutant melanoma cells” and BRAF wild type melanoma cells. Some of the current drugs can target the former much more effectively than the latter.

“When a cell divides and grows, the DNA inside will become tangled much like the way a rope will if you take it and keep turning it in circles […] To untangle the rope, you can either cut and join the rope or spend [a] long time turning it in opposite direction to untangle it,” says Karelia.

“The DNA has the same issue in our cells. To solve the problem, our bodies have a protein called topoisomerase, which cuts the DNA and joins it back to release the stress. What we show in this paper is this compound may be able to inhibit that activity of topo II alpha protein – the DNA is unable to unwind itself.”

Because of this anticarcinogenic mechanism, NISC-6 may also work in other types of cancer.

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