Mechanism of resistance identified

August 1, 2006

Organelles within the cell not only sequester cytotoxic drugs used in chemotherapy and prevent them from reaching the nucleus to do their job, once sequestered they go one step farther and shuttle the drugs entirely outside the cells.

Bethesda, Md. - Researchers at the National Cancer Institute (NCI) believe they have discovered why melanoma is so difficult to treat with anti-cancer drugs.

The answer lies in the melanosomes; those distinctive organelles within the cell not only sequester cytotoxic drugs used in chemotherapy and prevent them from reaching the nucleus to do their job, once sequestered they go one step farther and shuttle the drugs entirely outside the cells.

How cisplatin is foiled

Dr. Gottesman tells Dermatology Times that they found "a fairly dramatic reduction in uptake in the nucleus, which is where it normally goes and binds to DNA, but what looked like an increased uptake into melanosomes within the melanomas."

Dr. Gottesman says, "There have been indications that melanogenesis or melanosomes affected response to chemotherapy. I think this is the first direct evidence that the melanosomes are sequestering the drug."

"Platinum generally is not assumed to be bound to melanin. Other anthracycline drugs such as doxorubicin bind to melanin, so this is a bit unexpected. It turned out that it didn't matter whether the melanomas were pigmented or not, the drug seemed to accumulate in the melanosomes and the cells were resistant to it."

Only about 10 percent of the platinum was getting into the nucleus and perhaps half or more was sequestered in the melanosomes. This suggests a major mechanism of resistance to cisplatin, but perhaps not the only one.

Toxic intermediates are created during the process of pigmentation. Dr. Gottesman believes that the role of ABC transporters [ATP Binding Cassette (ATP-dependent) transporters] is to keep toxins within melanosomes, and not damage the cells. Cancer drugs such as cisplatin may resemble those naturally produced toxins and are pumped into melanosomes by ABC transporters, though this has not yet been demonstrated conclusively.

"The other interesting thing is that the melanosomes not only seemed to be taking up the drug, they also were spitting it out of the cell."

Dr. Gottesman says the evidence was in the culture medium, which became very dark with cell pigmentation.

"Part of the biology of melanocytes is that they are capable of transporting melanin-containing pigment granules to keratinocytes in the skin; that is why skin pigmentation occurs. So, resistance was due not only to the presence of melanosomes, which are structures that are capable of trapping all kinds of different compounds, but also there was an ability to get rid of the toxic materials by secreting the melanosomes."

Another curious finding was that the platinum dramatically increased the pigmentation of the cells.

He says, "We don't know if that was because of a proliferation of melanocytes or a stimulation of the pigmentation process, or if it is something to do with the toxic effect of the drug that stimulated genes that turned on melanocytes. But it looked like there was an inducible ability to respond to the toxic materials."

Implications for melanoma management

Dr. Gottesman says these discoveries of basic science are exciting because, "They suggest that if you block melanosomes development in melanomas, we might be able to reduce resistance to chemotherapy and allow the drugs to get to the nucleus."

Dr. Gottesman readily acknowledges, "We have a target now, but we are far from having drugs that we think we can use to manipulate the process."