Inhibition of the PI3K/AKT Pathway Sensitizes Oral Squamous Cell Carcinoma Cells to Anthracycline-Based Chemotherapy In Vitro

Abstract

Anthracycline-based chemotherapy, such as doxorubicin (Dox), while effective against many solid tumors, is not widely used for head and neck cancers. In this study, we evaluated the efficacy of Dox, and its derivative AD198 in human, canine, and feline oral squamous cell carcinomas cells (OSCC) in vitro. Dox and AD198 had significant an anti-proliferative effect on human, canine, and feline OSCC cells in dose-dependent manner. AD198 inhibited cell proliferation more effectively than Dox in tested OSCC cells. In the human oral squamous cell carcinoma SCC25 cells, Dox and AD198 increased the production of reactive oxygen species and subsequently increased apoptosis through activation of caspase signaling pathway. Dox and AD198 increased activation of AKT, ERK1/2, and p38 MAPK signaling pathways in tested OSCC cells by dose-dependent manner. The efficacy of Dox and AD198 treatments in inhibition of cell proliferation was increased in tested OSCC when combined with PI3K/AKT inhibitor, LY294002 treatment. Inhibition of PI3K/AKT reduced Dox- and AD198-induced activation of ERK1/2 and further increased Dox- and AD198-induced phosphorylation of p38 MAPK in OSCC. Our results suggest that the anthracycline therapies, such as Dox or AD198, can be more effective for treatment of OSCC when combined with inhibitors of the PI3K/AKT pathway.

Collective ERK/Akt activity waves orchestrate epithelial homeostasis by driving apoptosis-induced survival

“…Given a 24-hour cell cycle in MCF10A cells, which leads to ~4% population increase per hour, our observed apoptotic rate might be sufficient to maintain a steadystate balance between proliferation and death. Our mechanistic explanation about how inhibition of EGFR-ERK/Akt signaling together with a cytotoxic drug compromises EH and tissue integrity is consistent with numerous reports in which targeted therapies sensitize cancer cells to chemotherapeutic agents (Holt et al 2012;Smolensky et al 2017;Barbuti et al 2019). This provides a rationale to test further targeted/cytotoxic combination therapies to obtain better therapeutic responses for cancers.…”

Mitogen-activated protein kinase signaling pathway in oral cancer (Review)

“…Multiple signaling pathways may function in oncogenesis and in the growth of oral malignancies (4,5). Among these is the mitogen activated protein kinase (MAPK) signaling pathway, which regulates the expression of a large number of proteins involved in the control of cell proliferation, differentiation and apoptosis (6,7), and remains a focus of investigation for therapeutic targeting, along with the development of appropriate inhibitors (8).…”

Prognostic implications of the phosphatidylinositol 3-kinase/Akt signaling pathway in oral squamous cell carcinoma: overexpression of p-mTOR indicates an adverse prognosis

“…The phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signaling pathway plays important roles in regulating tumor cell survival, apoptosis, and protein translation [6,7]. PI3K is activated by receptor tyrosine kinases, leading to allosteric activation of the enzyme and tyrosine phosphorylation of its regulatory subunit.…”