PLGA-Disulfiram microparticles inhibit NF-κB and PD-L1 pathway and reverse chemoresistance induced by mesothelioma stem cells.


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Garima Tyagi1
1Wolverhampton university

Abstract

Background

Mesothelioma (MM) is a malignancy with < 12-month overall survival. Only one drug (Pemetrexed) is available for MM treatment. MM recurrence is very common due to chemoresistance caused by cancer stem cells (CSCs). Our previous publications demonstrate that hypoxia-induced NF-κB pathway activation plays a pivotal role in the maintenance of CSCs, chemo-radio-resistance and cancer metastasis. Hypoxia and NF-κB also induce PD-L1 expression in cancer allowing them to evade the host immune system. Development of a drug simultaneously targeting hypoxia-NF-κB-CSCs axis and PD-L1 is of clinical significance.

Our previous studies have shown that Disulfiram (DS) a clinically used anti-alcoholism drug, in combination with copper (Cu) has strong toxicity in CSCs from a wide range of cancer types. The clinical application of DS in cancer has been limited by its very short half-life (4 minutes) in the bloodstream. MM mainly infiltrates local organs and tissues with rare distant metastasis. Considering this growing feature of MM, we developed a biodegradable and controlled released poly (lactic-co-glycolic acid) microparticle-encapsulated Disulfiram (PLGA-DS) for local treatment of MM.

Method

MTT cytotoxicity assay, flow cytometry analysis of CSC markers, hypoxic cell cultures, western blot, stable over-expression and knock out of NF-κBp65, CSC sphere reformation, invasion/migration assay.

Results

Hypoxic culture significantly induces Pemetrexed and Cisplatin resistance in MM cell lines. Hypoxia-cultured cells showed high NF-κB expression, CSC markers and manifested strong migration/invasion ability. PLGA-DS showed strong toxicity to MM cell lines and reversed hypoxia-induced chemoresistance. PLGA-DS/Cu completely reversed hypoxia and CSC induced chemoresistance and abolished CSC population in culture. PLGA-DS inhibited the hypoxia-induced NF-κB and PD-L1 expression and blocked the migration/invasion ability. PLGA-DS/Cu also potentiates the cytotoxic effect of cisplatin/pemetrexed synergistically. The in vivo studies are ongoing.

Conclusion

DS is an FDA approved a drug with all safety data available. It can be quickly translated for the treatment of MM in clinics.