Metronomic Cordycepin Therapy Prolongs Survival of Oral Cancer-Bearing Mice and Inhibits Epithelial-Mesenchymal Transition

Abstract

Cordycepin (3′-deoxyadenosine) is a natural compound abundantly found in Cordyceps sinesis in natural and fermented sources. In this study, we examined the effects of cordycepin in a human oral squamous cell carcinoma (OSCC) xenograft model. Cordycepin was administered in a regular, low-dose and prolonged schedule metronomic therapy. Two doses of cordycepin (25 mg/kg, 50 mg/kg) were administrated five days a week for eight consecutive weeks. The tumor volumes were reduced and survival time was significantly prolonged from 30.3 ± 0.9 days (control group) to 56 days (50 mg/kg group, the day of tumor-bearing mice were sacrificed for welfare consideration). The weights of mice did not change and liver, renal, and hematologic functions were not compromised. Cordycepin inhibited the OSCC cell viability in vitro (IC50 122.4–125.2 μM). Furthermore, morphological characteristics of apoptosis, increased caspase-3 activity and G2/M cell cycle arrest were observed. In wound healing assay, cordycepin restrained the OSCC cell migration. Cordycepin upregulated E-cadherin and downregulated N-cadherin protein expression, implying inhibition of epithelial-mesenchymal transition (EMT). The immunohistochemical staining of xenograft tumor with E-cadherin and vimentin validated in vitro results. In conclusion, metronomic cordycepin therapy showed effective tumor control, prolonged survival and low toxicities. Cytotoxicity against cancer cells with apoptotic features and EMT inhibition were observed.

Cordycepin inhibits lipopolysaccharide-induced cell migration and invasion in human colorectal carcinoma HCT-116 cells through down-regulation of prostaglandin E2receptor EP4

“…1 ), but it did show anti-inflammatory activity. Previous studies have shown that cordycepin has anti-cancer effects in human breast cancer cells ( 29 ), human lung cancer cells ( 30 ), oral squamous cell carcinoma ( 31 ), and human bladder cancer cells ( 32 ). Cordycepin has also been shown to have anti-cancer effects in human colorectal cancer cells, but there have been few reports on cordycepin’s role in altering early events (i.e., migration and invasion) to prevent the progression into cell transformation.…”

Jam3 promotes migration and suppresses apoptosis of renal carcinoma cell lines

“…4A). Integrin β1 can induce cancer cell migration (19), and it was found that the protein level of integrin β1 was also reduced in the Jam3 siRNA group, compared with that in the control group (P<0.05; Fig. 4A).…”

Reversal of Epithelial–Mesenchymal Transition by Natural Anti-Inflammatory and Pro-Resolving Lipids

“…Cordycepin (25-100 µM) can inhibit cancer stemness of TGF-induced chemo-resistant ovarian cancer cells [137]. Metronomic cordycepin therapy (25 mg/kg and 50 mg/kg) can prolong the survival of oral cancer-bearing mice and it (50 µM) inhibit EMT [138]. Cordycepin (100-200 µM) suppresses integrin/FAK signaling and EMT in HCC [139].…”