Papaverin increases sensitivity of tumour cells to Radiotherapy
A new research published in Proceedings of the National Academy of Sciences shows that this primitive drug identified more than a century ago and used as a smooth-muscle relaxant may help sensitize the tumour cells more easily to radiotherapy.
The researchers found that papaverine inhibits the respiration of mitochondria, the oxygen-consuming and energy-making components of cells, and sensitizes model tumours to radiation. They found that the drug does not affect the radiation sensitivity of well-oxygenated normal tissues. Moreover, the investigators also described derivatives of papaverine that have the potential to become clinical radiosensitizers with potentially fewer side effects.
Radiation kills cancer cells in two ways: directly, by damaging DNA, and indirectly, by generating reactive, damage-causing molecules called oxygen radicals. Hypoxic conditions reduce the generation of radiation-induced DNA damage and the effective toxicity of a dose of radiation.
"We know that hypoxia limits the effectiveness of radiation therapy, and that's a serious clinical problem because more than half of all people with cancer receive radiation therapy at some point in their care," says principal investigator Nicholas Denko, Ph.D., MD, professor of radiation oncology at the OSUCCC - James.
"We found that one dose of papaverine prior to radiation therapy reduces mitochondrial respiration, alleviates hypoxia, and greatly enhances the responses of model tumors to radiation," Denko says.
Martin Benej and associates showed that hypoxic tumors can be sensitized to RT by targeting mitochondrial respiration.
The researchers identified the 150-year-old FDA-approved drug papaverine as a mitochondrial complex I inhibitor. A single dose of the drug prior to RT alleviates hypoxia in model tumors and strikingly enhances the response to RT. Well-oxygenated normal tissues are not radiosensitizer. Removal of papaverine’s phosphodiesterase 10A inhibitory activity by structural modification has identified the potentially safer generation of complex I-inhibiting radiosensitizers.
"If malignant cells in hypoxic areas of a tumor survive radiation therapy, they can become a source of tumor recurrence," Denko says. "It's critical that we find ways to overcome this form of treatment resistance."
Generally, radiologists focus on delivering more oxygen to the tumor but according to the investigators, these attempts have met with little clinical success because tumors have poorly formed vasculature.
"We took the opposite approach. Rather than attempting to increase oxygen supply, we reduced the oxygen demand, and these findings suggest that papaverine or a derivative is a promising metabolic radiosensitizer," he added.
Tumor hypoxia is a consequence of oxygen demand and supply. Cancer cells require high levels of oxygen to fuel their rapid growth, which can be so great that it outpaces the delivery of oxygen from the blood supply. Poorly formed blood vessels in the tumor are not efficient at delivering oxygen and other nutrients. Insufficient oxygen causes necrosis surrounded by areas of hypoxia. Cancer cells in hypoxic regions at a distance from the blood vessel can also be beyond the reach of chemotherapy and be resistant to radiation.
For reference log on to https://doi.org/10.1073/pnas.1808945115