Introduction: Despite improved therapeutics in oral squamous cell carcinoma (OSCC), tumor cells that are either quiescent and/or endowed with stem cell-like attributes usually survive treatment and recreate tumor load at relapse. Through this study, we aimed strategically to eliminate these stem cell-like cancer cells using a combination drug approach. Methods: Primary cultures from 15 well-moderately differentiated OSCC were established, and the existence of cancer cells with stem cell-like characteristics using five cancer stem cell (CSC) specific markers -CD44, CD133, CD147, C166, SOX2 and spheroid assay was ascertained. Next, we assessed quiescence in CSCs under normal and growth factor-deprived conditions using Ki67. Among several gene signatures regulating quiescent cellular state, we evaluated the effect of inhibiting Dyrk1b in combination with topoisomerase II and histone deacetylase inhibitors in targeting quiescent CSCs. Multiple drug-effect analysis was carried out with CompuSyn software to determine combination-index values. Results: We observed that CD44 + CD133 + showed the highest level of SOX2 expression. CSCs showed varying degrees of quiescence, and inhibition of Dyrk1b decreased quiescence and sensitized CSCs to apoptosis. In the drug-combination study, Dyrk1b inhibitor was combined with topoisomerase II and histone deacetylase inhibitors to target quiescent CSCs. In combination, a synergistic effect was seen even at a 16-fold lower dose than IC 50 . Furthermore, combined treatment decreased glutathione levels and increased ROS and mitochondrial stress, leading to increased DNA damage and cytochrome c in CSCs.
Conclusion:We report marker-based identification of CSC subpopulations and synergy of Dyrk1b inhibitor with topoisomerase II and HDAC inhibitors in primary OSCC. The results provide a new therapeutic strategy to minimize quiescence and target oral CSCs simultaneously.
Angiogenesis, the formation of new capillaries from pre-existing vessels, is essential for tumor progression. Synthetic derivatives of
anti-cancer compound, noscapine (an opium alkaloid) such as Cl-noscapine, Br-noscapine and Folate-noscapine along with two of the
reference compounds, TNP-470 and paclitaxel were examined for anti-angiogenic activities by using human umbilical vein endothelial
cells (HUVECs). The noscapine derivatives showed anti-angiogenic activity albeit at high concentration compared to the reference
compounds. All the tested compounds inhibited angiogenesis in a dose-dependent manner; the drug concentration causing 50%
inhibition of cell survival was 11.87 μM for Cl-noscapine, 6.9 μM for Br-noscapine and 6.79 μM for folate-noscapine. Besides, all the
noscapine derivatives significantly inhibited cord formation (IC50 for Cl-noscapine is 50.76 μM, for Br-noscapine is 90.08 μM and for
folate-noscapine is 18.44 μM) as well as migration and invasion (IC50 value of Cl-noscapine is 28.01 μM, for Br-noscapine is 19.78 μM
and for folate-noscapine is 10.76 μM) of endothelial cells. Based on these results, we speculated that the inhibitory effects on human
endothelial cell proliferation of noscapine derivatives might be important for anti-angiogenesis.
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