Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism

Abstract

Tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. An acute increase in tumor oxygenation before radiation treatment should therefore significantly improve the tumor cell kill after radiation. Efforts to increase oxygen delivery to the tumor have not shown positive clinical results. Here we show that targeting mitochondrial respiration results in a significant reduction of the tumor cells' demand for oxygen, leading to increased tumor oxygenation and radiation response. We identified an activity of the FDA-approved drug papaverine as an inhibitor of mitochondrial complex I. We also provide genetic evidence that papaverine's complex I inhibition is directly responsible for increased oxygenation and enhanced radiation response. Furthermore, we describe derivatives of papaverine that have the potential to become clinical radiosensitizers with potentially fewer side effects. Importantly, this radiosensitizing strategy will not sensitize well-oxygenated normal tissue, thereby increasing the therapeutic index of radiotherapy.

A potential solution for eliminating hypoxia as a cause for radioresistance

“…Further, we predicted that only a 30% reduction in oxygen consumption rate would be sufficient to eliminate hypoxia. Here, Benej et al (1) demonstrate that a 30 to 50% reduction in oxygen consumption rate is achievable in the clinically relevant papavarine dose range (1 to 10 μM). Thus, papavarine or its derivatives should effectively reduce hypoxia at clinically achievable doses.…”

“…Despite the clear evidence that hypoxia is deleterious for achieving local tumor control and better survival after radiotherapy, there is no established method for reducing or eliminating it. In PNAS, Benej et al (1) describe a class of hypoxic radiosensitizers that decreases hypoxia by blocking mitochondrial complex 1 to inhibit oxygen consumption rate. The lead compound is papavarine, a drug approved by the Food and Drug Administration to treat erectile dysfunction and vasospasm.…”

“…At baseline, the hypoxic fraction (percent volume <1 mmHg) is ∼12%. of papavarine or its derivatives, in comparison with others in this class (1). Nevertheless, it will be imperative to rule out the possibility of cumulative toxicity in preclinical studies, preferably before conducting clinical trials.…”

“…In summary, the paper by Benej et al (1) represents a potential landmark in the six-decade-old quest to eliminate hypoxia as a cause for radiotherapy treatment failure. To avoid the pitfalls of prior trials, hypoxia-imaging methods should be used before and after drug administration to verify that patients have hypoxic tumors before treatment and that the drug effectively reduces it.…”

Clinical Limitations of Photon, Proton and Carbon Ion Therapy for Pancreatic Cancer

“…Recent advancements in delivery, image guidance and planning have guided novel techniques of radiation dose escalation. Stereotactic body radiation therapy (SBRT) allows larger doses of up to 25 Gy per fraction to be delivered (as opposed to 2 Gy per fraction), increasing the radiobiological effectiveness of XRT. However, due to the anatomical location of the pancreas and proximity to critical normal structures, doses required to provide sufficient LC are still prohibitive [10].…”