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05.12.2018 | Original Article

Targeted disruption of PI3K/Akt/mTOR signaling pathway, via PI3K inhibitors, promotes growth inhibitory effects in oral cancer cells

Zeitschrift:
Cancer Chemotherapy and Pharmacology
Autoren:
Sadhna Aggarwal, Sarah John, Leena Sapra, Suresh C. Sharma, Satya N. Das
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00280-018-3746-x) contains supplementary material, which is available to authorized users.
Sadhna Aggarwal and Sarah John: equal contribution as first author.

Abstract

Purpose

The phosphoinositide-3-kinase (PI3K) pathway is the frequently altered in human cancer. This has led to the development and study of novel PI3K inhibitors for targeted therapy and also to overcome resistance to radiotherapy.

Method

The anti-tumour effects of PI3K inhibitors (PI-828, PI-103 and PX-866) in terms of cell proliferation, colony formation, induction of apoptosis, cell cycle arrest, invasion, autophagy, and pNF-κB/p65 translocation in SCC-4, SCC-9 and SCC-25 cells were studied by performing MTT, clonogenic, DAPI staining, propidium iodide staining, annexin-V binding, matrigel invasion, acridine orange staining and immuno-fluorescence assay. Western blot assay was performed to assess the alteration in the expression of various proteins.

Result

PI-828 and PI-103 treatment exhibited dose-dependent inhibition of growth and proliferation of OSCC cells with a concomitant induction of apoptosis, altered cell cycle regulation and decreased invasiveness (p < 0.01). PX-866 induced apoptosis, cell cycle arrest, autophagy and a significant decrease in the invasiveness of oral cancer cells as compared to untreated cells (p < 0.01). These compounds significantly reduced expression of COX-2, cyclin-D1 and VEGF in the treated cells besides cytoplasmic accumulation of pNF-κB/p65 protein. In addition to PI3Kα, inactivation of downstream components, i.e. Akt and mTOR was seen.

Conclusion

PI3K inhibitors such as PI-103, PI-828 and PX-866 may be developed as potential therapeutic agents for effective treatment of oral squamous cell carcinoma (OSCC) patients, associated with activated PI3K/Akt pathway.

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Zusatzmaterial
Supplementary Fig. 1: (a) Photomicrographs and (b) bar graphs as obtained after In vitro clonogenic assay indicating growth inhibitory effects of PI3K inhibitors (IC 50) treatment on oral cancer cell lines (SCC-4, SCC-9 and SCC-25 cells) (PPT 1397 KB)
280_2018_3746_MOESM1_ESM.ppt
Supplementary Fig. 2: Representative photomicrographs showing nuclear DNA fragmentation of PI-103, PI-828 and PX-866 treated SCC-4 cells in comparison to normal nuclear DNA in untreated SCC-4 cells (Blue: DAPI stain) (PPT 1629 KB)
280_2018_3746_MOESM2_ESM.ppt
Literatur
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