Polyethylenimine, an Autophagy-Inducing Platinum-Carbene-Based Drug Carrier with Potent Toxicity towards Glioblastoma Cancer Stem Cells

SIMPLE SUMMARY: The resistance of tumours to treatment and their tendency to reoccur following successful treatment are major problems for long-term cancer patient survival. Research has identified a special subset of cells in tumours with stem-cell-like properties to be at the heart of this problem. Thus, the development of new chemotherapeutic compounds with unique characteristics that may target this subset of cancer cells is of great interest in the pursuit of more effective cancer treatments. This work describes one such compound, being a new platinum-based compound attached to a long polymer molecule in order to enhance its anti-cancer properties. Importantly, the stem-cell-like subset of cells seems to be considerably more sensitive to the toxicity of the polymer itself than the bulk of tumour cells, with an interesting mode of cell death which has characteristics different to that of more “classical” anti-cancer therapeutics. ABSTRACT: The difficulty involved in the treatment of many tumours due to their recurrence and resistance to chemotherapy is tightly linked to the presence of cancer stem cells (CSCs). This CSC sub-population is distinct from the majority of cancer cells of the tumour bulk. Indeed, CSCs have increased mitochondrial mass that has been linked to increased sensitivity to mitochondrial targeting compounds. Thus, a platinum-based polyethylenimine (PEI) polymer–drug conjugate (PDC) was assessed as a potential anti-CSC therapeutic since it has previously displayed mitochondrial accumulation. Our results show that CSCs have increased specific sensitivity to the PEI carrier and to the PDC. The mechanism of cell death seems to be necrotic in nature, with an absence of apoptotic markers. Cell death is accompanied by the induction of a protective autophagy. The interference in the balance of this pathway, which is highly important for CSCs, may be responsible for a partial reversion of the stem-like phenotype observed with prolonged PEI and PDC treatment. Several markers also indicate the cell death mode to be capable of inducing an anti-cancer immune response. This study thus indicates the potential therapeutic perspectives of polycations against CSCs.