Temozolomide , or TMZ , is a chemotherapy agent used to treat glioblastoma. TMZ causes DNA damage that results in tumor cell apoptosis and thereby increases the survival rate of patients with glioblastoma. Over time, however, glioblastoma cells can become less responsive to TMZ because the drug induces autophagy in these cells, clearing otherwise toxic cargo and saving the cells from premature death. This chemoresistance can prove fatal for patients who rely on the anti-cancer effects of TMZ.
Now, researchers have discovered a way to keep TMZ working long-term: by combining it with the cholesterol-reducing statin simvastatin , or Simva.
Previous studies have shown that long-term consumption of statins prior to or in addition to cancer therapeutics can increase the survival rates of patients with different forms of cancer. Simva is shown to be less toxic towards the liver and gastrointestinal tract than other statins and can cross the blood-brain barrier to target glioblastoma cells.
The research team showed that the incubation of cells with both Simva and TMZ significantly increased the number of cells undergoing apoptosis versus cells treated with TMZ alone. That was true for glioblastoma cell lines and cells gathered from patients with glioblastoma.
Importantly, the incubation of cells with intermediate metabolites of the mevalonate pathway, the target of cholesterol biosynthesis-blocking statins, failed to rescue the decrease in cell viability induced by the combined Simva–TMZ treatment. Thus, in addition to a reduction in blood cholesterol levels, Simva has novel pleiotropic effects in brain cancer.
Based on the team’s findings, Simva counteracts resistance to TMZ by disrupting the autophagy process, namely, the fusion step from autophagosomes to lysosomes. This step leads to the clearance of damaged intracellular organelles from cancer cells. Blocking this important protective mechanism, Simva facilitates TMZ killing of glioblastoma cells.
Because the observed effects are confined to 2D and 3D models of glioblastoma, it’s unclear how they’ll carry over to live organisms. This is currently addressed in work on xenograft mouse models. Combined with the results of the current study, those findings could offer exciting new ways to harness the synergistic effects of Simva to boost TMZ chemotherapy.