The frequent emergence of anticancer drug resistance continues to be a major impediment towards curative chemotherapy of various human cancers.
Multidrug resistance (MDR) to multiple anticancer drugs is perhaps the most extensively studied major mechanism of anticancer drug resistance. MDR is mediated by efflux transporters (plasma membrane proteins that extrude various cytotoxic molecules out of cells) called ABC superfamily, recognizing a wide range of structurally and mechanistically distinct chemotherapeutic agents. When overexpressed in the plasma membrane of cancer cells, these efflux pumps, expel structurally distinct cytotoxic drugs, such as chemotherapeutic agents in cancer cells (e.g. the ABCG2 efflux transporter in acute myeloid leukemia cells-AML). MDR tumor cells with efflux transporter overexpression possess an increased number of lysosomes per cell as a second line of defence for lysosomal entrapment of hydrophobic weak base anticancer drugs. The new invention focuses on Imidazoacridinones (IAs), a novel class of fluorescent molecules which differ in their residues and are recognized and expelled out of tumor cells by ABC transporters like ABCG2, and/or sequestered within lysosomes. Some of these IAs have been developed as experimental anticancer drugs. Taking advantage of the increased number of lysosomes in MDR cancer cells, IAs sequestration in lysosomes and their light sensitive nature, the current novel therapeutic approach is essentially a pharmacological Trojan horse activated by light. This results in the rapid eradication of the cancer cells and the tumor. This photodynamic therapy (PDT) approach was shown to be effective and selective to MDR cancers when compared to healthy tissues.
- Internal, rapid eradication of the cancer cells and the tumor.
- Effective and selective to MDR cancers
Applications and Opportunities
- Eradication of various carcinomas with increased number of lysosomes.
- Eradication of various carcinomas exhibiting a MDR phenotype i.e. cancer patients failing first line or second line treatments hence exhibiting chemoresistance.