Redaporfin Development for Photodynamic Therapy and its Combination with Glycolysis Inhibitors^†

Abstract

Photodynamic therapy (PDT) remains an underutilized treatment modality in oncology. Many efforts have been dedicated to the development of better photosensitizers, better formulations and delivery methods, rigorous planning of light dose distribution in tissues, mechanistic insight, improvement of treatment protocols and combinations with other therapeutic agents. Hopefully, progress in all these fields will eventually expand the use of PDT. Here we offer a brief review of our own contribution to the development of a photosensitizer for PDTredaporfincurrently in Phase II clinical trials, and present data on its combination with two glycolysis inhibitors: 2-deoxyglucose and 3-bromopyruvate. We show that 3-bromopyruvate is more cytotoxic to a carcinoma cell line (CT26) than to a normal fibroblast (3T3) cell line, and that this selectivity is maintained in the in vitro combination with redaporfin-PDT. This combination was investigated in BALB/c mice with large subcutaneous CT26 tumors and it is shown that the cure rate in the combination is higher (33% cures) than in PDT (11% cures) or in 3-bromopyruvate (no cures) alone. The combination of redaporfin-PDT with 3bromopyruvate illustrates the potential of combination therapies and how PDT benefits can be enhanced by systemic drugs with complementary targets.

Photodynamic Therapy: From the Basics to the Current Progress of N-Heterocyclic-Bearing Dyes as Effective Photosensitizers

“…In addition, Karwicka et al found that depriving the tumor of blood supply using this PS molecule led to a highly effective antineoplastic response in vivo , with tumors not reappearing in 67% of mice after more than a year [ 207 ]. Lastly, Mendes and Arnaut explored the potential of combining Redaporfin with glycolysis inhibitors 3-bromopyruvate and 2-deoxyglucose [ 208 ] ( Figure 9 ). The authors explain that glucose transporters serve cells to absorb glucose and 2-deoxyglucose, which is analogous to glucose but cannot be metabolized.…”

“… Role of glycolysis inhibitors combined with the photodynamic activity of Redaporfin in developing an efficient antitumor strategy proposed by Mendes and Arnaut [ 208 ]. 2-Deoxyglucose acts as an inhibitor of hexokinase and phosphoglucose isomerase, while 3-bromopiruvato is uptaken by cells through monocarboxylate transporters, which are overexpressed in tumor cells, targeting hexokinase and glyceraldehyde-3-phosphate dehydrogenase enzymes, both of which are decisive for the glycolytic pathway’s regulation.…”