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| Image credit – National Institutes of Health |
Thrust into the headlines at the beginning of the COVID-19 pandemic as a potential treatment promoted by the former president of the US, hydroxychloroquine has been shown to breakdown tumor resistance to the chemotherapy drug cisplatin, long used to treat a variety of cancers, including head and neck cancers.
The study results appeared March 14, 2022 in the Proceedings of the National Academy of Sciences."Cisplatin is a very important chemotherapy drug, but tumor resistance to cisplatin is a huge problem,” said co-senior author Umamaheswar Duvvuri, M.D., Ph.D., head and neck surgeon at UPMC Hillman Cancer Center. “My lab is interested in understanding the mechanisms of resistance so that we can find better ways to treat these patients.”
In previous research a protein called TMEM16A was demonstrated to played a role in making tumors resistant to cisplatin, a chemotherapy drug used to treat testicular, ovarian, cervical, bladder, lung and head and neck cancers.
In the new study, Duvvuri and colleagues showed that TMEM16A is overproduced in tumors, which in turn overproduce structures within cells, called lysosomes, which straddle the cell’s outer membrane. In healthy cells, enzymes inside lysosomes act to break down worn out cell parts so that they can be reused or pumped out of the cell to be discarded as waste.
It has been a puzzle to scientists who have observed that these lysosomes are over-produced in cancerous tumors, however finding that TMEM16A plays a critical role in this overproduction, the researchers began looking for ways to block or inhibit lysosomal function.
The anti-malarial drug hydroxychloroquine was an ideal candidate as it has long been found effective in decreasing lysosomal function. Working first in laboratory and then mouse models, the researchers found that using hydroxychloroquine in conjunction with cisplatin slowed tumor growth more than either drug alone.
“These experiments suggest that hydroxychloroquine has a synergistic effect with cisplatin,” explained Duvvuri. “This is relevant for patients because repurposing hydroxychloroquine, which is an existing drug, will allow us to translate these findings to the clinic much faster than we could with a novel compound.”
In previous research a protein called TMEM16A was demonstrated to played a role in making tumors resistant to cisplatin, a chemotherapy drug used to treat testicular, ovarian, cervical, bladder, lung and head and neck cancers.
In the new study, Duvvuri and colleagues showed that TMEM16A is overproduced in tumors, which in turn overproduce structures within cells, called lysosomes, which straddle the cell’s outer membrane. In healthy cells, enzymes inside lysosomes act to break down worn out cell parts so that they can be reused or pumped out of the cell to be discarded as waste.
It has been a puzzle to scientists who have observed that these lysosomes are over-produced in cancerous tumors, however finding that TMEM16A plays a critical role in this overproduction, the researchers began looking for ways to block or inhibit lysosomal function.
The anti-malarial drug hydroxychloroquine was an ideal candidate as it has long been found effective in decreasing lysosomal function. Working first in laboratory and then mouse models, the researchers found that using hydroxychloroquine in conjunction with cisplatin slowed tumor growth more than either drug alone.
“These experiments suggest that hydroxychloroquine has a synergistic effect with cisplatin,” explained Duvvuri. “This is relevant for patients because repurposing hydroxychloroquine, which is an existing drug, will allow us to translate these findings to the clinic much faster than we could with a novel compound.”
Source: University of Pittsburgh Medical Center press release
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