Uttroside B, a US FDA-designated ‘Orphan Drug’, mitigates the development of hepatocellular carcinoma and its pulmonary metastasis via EGFR/ERK-mediated inhibition of SREBP-1 and STAT-3

Hepatocellular carcinoma (HCC) is a highly aggressive tumor with rapid propensity for extrahepatic metastasis, which critically limits long-term clinical benefits of conventional chemotherapeutics and decreases the overall survival rate of patients. Our previous reports have documented the anti-HCC potential and pharmacological safety of uttroside B (Utt-B). Herein, we illustrate the role of EGFR/ERK signaling axis and their downstream targets SREBP-1 and STAT-3, in the action mechanism of Utt-B. Further, the current study also demonstrates the strong anti-invasive and anti-metastatic properties of Utt-B against liver cancer. Pharmacological inhibition of EGFR/ERK axis led to the abrogation of Utt-B-mediated cytotoxicity and induction of apoptosis, in vitro. siRNA-mediated silencing of EGFR resulted in the attenuation of the cytotoxic, pro-apoptotic and anti-invasive effects of Utt-B, in vitro, thereby validating the regulatory role of EGFR in orchestrating the anti-HCC and anti-metastatic potential of Utt-B. In vivo studies confirmed that treatment with Utt-B mitigates the development of primary hepatic tumors in an orthotopic xenograft model and impedes the pulmonary metastasis of HCC in a murine metastasis model, via the down-regulation of EGFR/ERK axis. Taken together, the current findings attest to the exceptional therapeutic potential of Utt-B against primary and metastatic HCC and highlight its potential as a candidate drug to be evaluated in the clinics for the benefit of HCC patients having limited prognosis and therapeutic options. (Figure presented.)