New Autophagy Inhibitors Block Cancer Growth in Animal Models

A recent paper described the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo.

The new compounds are based on the veteran antimalarial drug hydroxychloroquine (HCQ). HCQ is a lipophilic weak base and easily passes through plasma membranes. The free base form accumulates in lysosomes (acidic cytoplasmic vesicles) and is then protonated, resulting in concentrations within lysosomes up to 1000 times higher than in culture media. This increases the pH of the lysosome from four to six. Alteration in pH causes inhibition of lysosomal acidic proteases causing a diminished proteolysis effect. Higher pH within lysosomes causes decreased intracellular processing, glycosylation, and secretion of proteins with many immunologic and nonimmunologic consequences.

The developers of the new reagents – investigators at the University of Pennsylvania (Philadelphia, USA) – sought to improve the antiautophagic and anticancer properties of HCQ, since clinical studies have shown that it was not always possible to give patients a high enough dose of hydroxychloroquine to have an effect on their tumor cells.

In a paper published in the May 7, 2012, online edition of the journal Proceedings of the National Academy of Sciences of the USA the investigators described the benefits of their new bisaminoquinoline autophagy inhibitors that potently inhibited autophagy and impair tumor growth in vivo. The structural motifs that were necessary for improved autophagy inhibition compared with HCQ included the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, was a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulated within and deacidified the lysosome, resulting in impaired autophagy and tumor growth.

The compound Lys05 differed from HCQ - which has little impact on tumor cells when used as a single agent - by slowing tumor growth in animal models even in the absence of other antitumor therapies. Furthermore, the doses of Lys05 that were toxic to cancer cells had little or no effect on healthy cells.

“We see that Lys05 has antitumor activity at doses that are nontoxic for the animals,” said senior author Dr. Ravi K. Amaravadi, assistant professor of medicine at the University of Pennsylvania. “This single-agent antitumor activity suggests this drug, or its derivative, may be even more effective in patients than hydroxychloroquine.”

Initiation of clinical trials of Lys05 in human patients will require partnering with a major pharmaceutical company.

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