Uttroside B, a US FDA-designated Orphan drug, mitigates thedevelopment 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 the long-term clinical benefits of conventional chemotherapeutics and decreases the overall survival rate of patients. Our previous findings on the exceptional anti-HCC potential and pharmacological safety of uttroside B (Utt-B) have gained multiple international patents and the compound has been designated as an Orphan Drug against HCC by the US FDA. The current study substantiates the pharmacodynamics of Utt-B and is the first report to date on the anti-metastatic potential of the compound against HCC. Herein, we demonstrate the role of EGFR/ERK signaling axis and their downstream targets SREBP-1 and STAT-3, the key regulators of HCC development and the pulmonary metastasis, respectively, in orchestrating the anti-HCC and anti-metastatic potential of Utt-B. This is evidenced by the abrogation of the cytotoxic and pro-apoptotic effects of Utt-B upon pharmacological inhibition of this signaling axis. Orthotopic xenograft studies validated that Utt-B treatment restricted the development of tumors via the down-regulation of EGFR/ERK axis. Notably, Utt-B diminishes the migratory and invasive properties of liver cancer cells in vitro and impedes the pulmonary metastasis of HCC, in vivo. 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.