Targeting tumour energy metabolism potentiates the cytotoxicity of 5-aminolevulinic acid photodynamic therapy

Abstract

Background:Cancerous cells usually exhibit increased aerobic glycolysis, compared with normal tissue (the Warburg effect), making this pathway an attractive therapeutic target.Methods:Cell viability, cell number, clonogenic assay, reactive oxygen (ROS), ATP, and apoptosis were assayed in MCF-7 tumour cells and corresponding primary human mammary epithelial cells (HMEC).Results:Combining the glycolysis inhibitors 2-deoxyglucose (2DG; 180 mM) or lonidamine (300 μM) with 10 J cm−2 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) increases MCF-7 cytotoxicity (by 3.5-fold to 70% death after 24 h, and by 10-fold in 9-day clonogenic assays). However, glycolysis inhibition only slightly increases HMEC PDT cytotoxicity (between two-fold and three-fold to a maximum of 9% death after 24 h). The potentiation of PDT cytotoxicity only occurred if the glycolysis inhibitors were added after ALA incubation, as they inhibited intracellular accumulation of photosensitiser if coincubated with ALA.Conclusion:As 2DG and lonidamine are already used as cancer chemotherapeutic agents, our results are directly translatable to combination therapies with existing topical PDT.

2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy

“…However, it is also their weakness because inhibiting this process may cause death. Safe and efficient inhibition of glycolysis is a promising anticancer therapy, either by itself, or in combination with radiotherapy or chemotherapy [16].…”

“…Because 2DG inhibits the first critical steps at the beginning of glucose metabolism, both glycolysis and OXPHOS may be partially disrupted [44]. These events lead to decreased ATP production, blocked cell cycle, decreased and inhibited cell growth and even cell death [6,16,40].…”

Real-time Measurements of Amino Acid and Protein Hydroperoxides Using Coumarin Boronic Acid

“…Aminoleuvlinic acid is a heme precursor pro-drug that is preferentially taken up by tumor cells and converted to protoporphyrin IX in the mitochondria (52,53). Selective inactivation of tumor cells during aminoleuvlinic acid/photodynamic therapy has been attributed to 1 O 2 -mediated oxidative damage to mitochondrial proteins (53)(54)(55). Very little information with regard to oxidation of specific proteins or specific sites of oxidation is known, although the generally accepted mechanism includes peroxidation of lipids and proteins (51).…”

Effect of Lonidamine on Systemic Therapy of DB-1 Human Melanoma Xenografts with Temozolomide

“…We wanted to exploit this natural preference of tumors for glycolytic metabolism as a method to selectively induce intracellular acidification of the tumor by accumulation of lactic acid even under aerobic conditions and use this selective tumor acidification and de-energization to enhance tumor response to chemotherapeutic agents, such as N-mustards and doxorubicin (11)(12)(13)(14)(15). Others had shown that LND sensitizes tumors to hyperthermia (23)(24)(25)(26), radiotherapy (27,28) and photodynamic therapy (29) by a variety of different mechanisms. In addition, to selectively acidifying and deenergizing human melanoma xenografts, LND had similar effects on mouse xenografts of triply-negative and triplypositive human breast cancer, human ovarian cancer and human prostate cancer (12), with the effect of LND increasing with the extent of glycolytic metabolism in the tumor.…”