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Macroautophagy (hereafter referred to as "autophagy") is an evolutionarily conserved process to eliminate damaged proteins, protein complexes, and organelles in the cell. Therefore, the autophagic machinery facilitates cell survival under stressful circumstances, including tumor cells, which experience metabolic stress. However, the only FDA-approved drug to inhibit autophagy is Hydroxychloroquine (HCQ), but its use is limited due to its low potency and side effects at therapeutically relevant dosages.
The objective of this study was to determine whether the novel autophagy inhibitors Lys05 and SBI-0206965 could sensitize more potently established head and neck squamous cell carcinoma (HNSCC) cell lines CAL27 and FaDu to the effects of Cisplatin and radiotherapy than HCQ.

Cell viability and wound healing assay of the HNSCC cell lines CAL27 (tongue) and FaDu (hypopharynx) treated with the autophagy inhibitors Lys05 and SBI-0206965 only and combined with Cisplatin and/or radiotherapy were assessed. Additionally, synergistic or additive antitumor effects of the therapy combinations were assessed. Moreover, the effect on cell viability after treatment was also investigated in 3D spheroids comprised of CAL27 and FaDu grown in ultra-low attachment plates.

Lys05 and SBI-0206965 showed an IC50 at 4uM, whereas the IC50 of HCQ varied between 20 to 60uM depending on the cell line. Cell migration was inhibited with novel drugs at doses ranging between 1 to 3uM. In comparison, HCQ could only inhibit cell migration at dosages between 10 and 50uM. Furthermore, chemotherapy - comprised of autophagy inhibition and Cisplatin - and radiotherapy combined showed a significant decrease in cell viability in 2D and 3D cell culture.

Chemically targeting autophagy with specific inhibitors in established HNSCC cell lines shows significant reduction of cell viability and impairment of cancer cell migration.