Identification of a novel inhibitor of liver cancer cell invasion and proliferation through regulation of Akt and Twist1

Abstract

When primary cancer faces limited oxygen and nutrient supply, it undergoes an epithelial–mesenchymal transition, which increases cancer cell motility and invasiveness. The migratory and invasive cancer cells often exert aggressive cancer development or even cancer metastasis. In this study, we investigated a novel compound, 3-acetyl-5,8-dichloro-2-((2,4-dichlorophenyl)amino)quinolin-4(1H)-one (ADQ), that showed significant suppression of wound healing and cellular invasion. This compound also inhibited anchorage-independent cell growth, multicellular tumor spheroid survival/invasion, and metalloprotease activities. The anti-proliferative effects of ADQ were mediated by inhibition of the Akt pathway. In addition, ADQ reduced the expression of mesenchymal markers of cancer cells, which was associated with the suppressed expression of Twist1. In conclusion, ADQ successfully suppressed carcinogenic activity by inhibiting the Akt signaling pathway and Twist1, which suggests that ADQ may be an efficient candidate for cancer drug development.

Twist1 as a target for prevention of cutaneous squamous cell carcinoma

“…ADQ was shown to reduce Twist1 and increase E‐cadherin protein levels but did not affect transcription of the Twist1 gene 163 . Interestingly, ADQ also inhibits the Akt pathway, but this effect appears to be distinct from its anti‐Twist1 activity 163 in contrast with findings by Way et al which showed that emodin suppressed Twist1‐induced Akt activation 156 …”

“…and increase E-cadherin protein levels but did not affect transcription of the Twist1 gene. 163 Interestingly, ADQ also inhibits the Akt pathway, but this effect appears to be distinct from its anti-Twist1 activity 163 in contrast with findings by Way et al which showed that emodin suppressed Twist1-induced Akt activation. 156 While most identified Twist1 inhibitors reduce Twist1 protein level but not mRNA levels, the monoterpene thymoquinone, found in abundance in the seeds of the black caraway plant (Nigella sativa), 164 was revealed to deplete CD44 + breast cancer stem cells and reduce Twist1 gene expression by nearly 80% in MCF-7 breast cancer cells.…”

“…The novel compound ADQ (3‐acetyl‐5,8‐dichloro‐2‐((2,4‐dichlorophenyl)amino)quinolin‐4(1H)‐one) has been shown by Ha et al to prevent activities associated with metastasis including invasion, wound healing, and anchorage‐independent growth in several liver cancer cell lines 163 . ADQ was shown to reduce Twist1 and increase E‐cadherin protein levels but did not affect transcription of the Twist1 gene 163 .…”

“…The novel compound ADQ (3‐acetyl‐5,8‐dichloro‐2‐((2,4‐dichlorophenyl)amino)quinolin‐4(1H)‐one) has been shown by Ha et al to prevent activities associated with metastasis including invasion, wound healing, and anchorage‐independent growth in several liver cancer cell lines 163 . ADQ was shown to reduce Twist1 and increase E‐cadherin protein levels but did not affect transcription of the Twist1 gene 163 . Interestingly, ADQ also inhibits the Akt pathway, but this effect appears to be distinct from its anti‐Twist1 activity 163 in contrast with findings by Way et al which showed that emodin suppressed Twist1‐induced Akt activation 156 …”

“…159 invasion, wound healing, and anchorage-independent growth in several liver cancer cell lines. 163 ADQ was shown to reduce Twist1…”