Effects of Drugs Targeting Mitochondrial Respiration in Melanoma

Despite relying on glycolysis, there is growing evidence that many tumor types still have high levels of mitochondrial energy metabolism and functioning oxidative phosphorylation. One such subset of tumors is melanoma, potentially playing a role in both tumor progression and resistance to therapy. This has led researchers to wonder whether targeting mitochondrial respiration could be an effective way of fighting off its cancer effects.

A recent study from Biomolecules examined several different drugs and their specific effects on mitochondrial respiration, as well as the proliferation of melanoma cells and human dermal fibroblasts. The drugs included the antibiotics tigecycline, doxycycline, and azithromycin, the antiparasitic agent drug pyrvinium pamoate, and the anti-cancer agent ONC212. While overall these agents showed mixed results, the researchers believe they found one with promising results for targeting mitochondrial respiration while also helping to inhibit cancer cells.

The investigators found that the effects of tigecycline, doxycycline, and azithromycin on mitochondrial respiration in melanoma varied. The dose of azithromycin they studied showed very little impact on mitochondrial respiration, as well as very little impact on growth and cellular proliferation. Tigecycline and doxycycline were more effective in slowing proliferation, with tigecycline doing a better job of suppressing proliferation and respiration of both melanoma cells and human dermal fibroblasts. However, the study notes the potential for troubling effects from long-term antibiotic use during cancer, citing studies that suggest it can increase cancer risk and reduce progression-free survival in patients with cancer receiving treatment with immune checkpoint inhibitors.

Pyrvinium pamoate showed the ability to stifle mitochondrial respiration, but the researchers fear it brings a unique set of risks. Pyrvinium pamoate is able to induce dysfunction of oxidative phosphorylation and can inhibit proliferation. The toxicity associated with the treatment proved concerning, however. This drug is administered orally to treat the side effects of gastrointestinal parasites. The researchers speculate that oral use would not be effective for inhibiting tumor growth, and having it circulating in the blood could lead to toxicity.

The researchers also studied the anti-cancer agent ONC212, which was recently shown to reduce mitochondrial respiration in breast cancer, lymphoma, and glioblastoma. They found similar results in melanoma, lowering mitochondrial basal respiration, ATP-linked respiration, and maximal respiration in cancer cells. They found that ONC212 directly reduced enzymatic activity in most oxidative phosphorylation complexes.

Ultimately, the researchers propose ONC212 to be the most overall effective of these drugs, not only doing a superior job of lowering mitochondrial respiration but also bringing less risk with it than the antibiotics or pyrvinium pamoate. They conclude that it has the potential to be incorporated into a regimen as a targeted mitochondrial therapeutic in tandem with more standard melanoma therapy.

Reference

Aminzadeh-Gohari S, Weber DD, Catalano L, Feichtinger RG, Kofler B, Lang R. Targeting mitochondria in melanoma. Biomolecules. 2020;10(10):1395. doi:10.3390/biom10101395