Deguelin Potentiates Apoptotic Activity of an EGFR Tyrosine Kinase Inhibitor (AG1478) in PIK3CA-Mutated Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is known to be intrinsically resistant to inhibitors for epidermal growth factor receptor (EGFR). Until now, clinical outcomes for HNSCC using EGFR inhibitors as single agents have yielded disappointing results. Here, we aimed to study whether combinatorial treatment using AG1478 (EGFR tyrosine kinase inhibitor) and deguelin, which is a rotenoid isolated from the African plant Mundulea sericea, could enhance the anti-tumor effects of AG1478 in HNSCC. For Ca9-22 cells with EGFR, KRAS, and PIK3CA wild types, AG1478 alone suppressed both phosphorylated levels of ERK and AKT and induced apoptosis. On the contrary, for HSC-4 cells with EGFR and KRAS wild types, and a PIK3CA mutant, AG1478 alone did not suppress the phosphorylated level of AKT nor induce apoptosis, while it suppressed ERK phosphorylation. Forced expression of constitutively active PIK3CA (G1633A mutation) significantly reduced the apoptotic effect of AG1478 on the PIK3CA wild-type Ca9-22 cells. When HSC-4 cells with the PIK3CA G1633A mutation were treated with a combination of AG1478 and deguelin, combination effects on apoptosis induction were observed through the inhibition of the AKT pathway. These results suggest that the combination of EGFR tyrosine kinase inhibitor with deguelin is a potential therapeutic approach to treat PIK3CA-mutated HNSCC.

Promising Biomarkers to Predict the Efficacy of Inhibitors of the Epidermal Growth Factor Receptor Tyrosine Kinase in Head and Neck Squamous Cell Carcinoma

“…These mutations may stimulate survival signals independent of EGFR activation by activating AKT [18], suggesting that mutated PIK3CA may be a reliable and promising biomarker predicting the sensitivity of EGFR TKI in HNSCC. This hypothesis has been supported by results showing that cells expressing wild type PIK3CA, but with a loss of PTEN, are not resistant to EGFR inhibitors [19], whereas cells expressing mutant PIK3CA and harboring wild type PTEN are resistant to EGFR TKIs [20]. Moreover, the combination of the anti-EGFR monoclonal antibody cetuximab and a PI3K TKI was reported to be a good therapeutic option in PIK3CA-mutated HNSCC [21].…”

The Natural Flavonoid Compound Deguelin Inhibits HCMV Lytic Replication within Fibroblasts

“…Deguelin has been studied for just over 20 years, and much of the work has focused on its potential use as an anti-cancer agent. More specifically, investigators have found deguelin displays anti-cancer activities both in vitro and in vivo for a variety of cancers across tissue types, including non-small cell lung cancer [ 22 , 23 , 24 , 25 ], triple negative breast cancer [ 26 , 27 ], prostate cancer [ 28 ], gastric cancer [ 29 , 30 , 31 ], hepatocellular carcinoma [ 32 , 33 ], esophageal squamous cell carcinoma [ 34 , 35 ], acute myeloid leukemia [ 36 , 37 , 38 , 39 ], pancreatic cancer [ 40 , 41 , 42 ], head and neck squamous cell carcinoma [ 43 , 44 , 45 ], lung squamous cell carcinoma [ 46 ], and androgen receptor-positive breast cancer [ 47 ]. Deguelin induces apoptosis in non-small cell lung cancer cells, for example, by repressing Noxa through B lymphoma Mo-MLV insertion region 1 homolog (BMI1) regulation [ 25 ].…”

The Natural Flavonoid Compound Deguelin Inhibits HCMV Lytic Replication within Fibroblasts

“…Deguelin has been studied for just over 20 years, and much of the work has focused on its potential use as an anti-cancer agent. More specifically, investigators have found deguelin displays anti-cancer activities both in vitro and in vivo for a variety of cancers across tissue types, including non-small cell lung cancer [19][20][21][22], triple negative breast cancer [23,24], prostate cancer [25], gastric cancer [26][27][28], hepatocellular carcinoma [29,30], esophageal squamous cell carcinoma [31,32], acute myeloid leukemia [33][34][35][36], pancreatic cancer [37][38][39], head and neck squamous cell carcinoma [40][41][42], lung squamous cell carcinoma [43], and androgen receptor-positive breast cancer [44]. Deguelin induces apoptosis in non-small cell lung cancer cells, for example, by repressing Noxa through Bmi1 regulation [22].…”