Papaverine is an FDA-approved potent inhibitor of mitochondrial complex I. Papaverine’s mitochondrial complex I inhibition has been shown to be responsible for increased oxygenation and enhanced radiation response. However, papaverine is also a phosphodiesterase 10A (PDE10A) inhibitor with potential side- effects on blood pressure and vascular tone, especially in patients with cardiovascular co-morbidities.

Problem

Tumor hypoxia poses a significant challenge for radiation therapy, dampening the efficacy of treatment and limiting the biologically effective dose. Hypoxic tumors are inherently resistant to treatment by radiotherapy. Although this has been known for over 50 years, there is not an efficient way to radiosensitize this subgroup of solid tumors. Hypoxia exists because of an inherent mismatch in the delivered oxygen versus the consumed oxygen within the tumor. Many groups have tried to deliver more oxygen to the tumor, but this has been ineffective clinically. Effective treatments that make the tumor cell to respond to radiotherapy are needed to improve patient outcomes.

Solution

Researchers at The Ohio State University have developed novel compounds that harness the power of mitochondrial respiration modulation to elevate tumor oxygenation and amplify the tumor’s response to radiation therapy. These novel derivatives of papaverine provide for a breakthrough radiosensitizing strategy by offering improved effectiveness with potentially fewer side effects. The novel compounds have been designed to separate the mitochondrial C1 inhibiting activity from the PDE10A inhibition activity, thus removing the side effects typically associated with papaverine. Crucially, this strategy selectively enhances radiation response in tumor cells while sparing well-oxygenated normal tissue, elevating the therapeutic index of radiotherapy.

Benefits/Advantages

• Selectively targeting mitochondria Complex 1 inhibition with reduced phosphodiesterase inhibition
• Enhanced Radiation Response
• Reduced Side Effects
• Elevated Therapeutic Index

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