Biology subjects

Anto, N. P.

Publications and source records attributed to Anto, N. P..

5 recordsLinked to original sources

bioRxiv2025

Evaluating the therapeutic efficacy of the US FDA-designated Orphan drug, uttroside B in impeding hepatocarcinogenesis via induction of immunogenic apoptosis, using a murine model of Aflatoxin B1-induced liver carcinogenesis

The sustained exposure to aflatoxin B1 (AFB1), a mycotoxin produced by Aspergillus sp., is one of the fundamental causes of hepatocellular carcinoma (HCC). We have previously documented the exceptional anti-HCC potential and pharmacological safety of uttroside B, a phytosaponin isolated in our lab (Utt-B). The current results indicate that Utt-B mitigates tumor development in mice that have been subjected to AFB1 exposure. Utt-B was found to be cytotoxic towards primary liver cancer cells cultured from mice bearing AFB1-induced liver tumors and the compound effectively prevented the formation of AfBO-DNA adducts in AFB1-induced liver tumors as well as primary liver cancer cells. In vitro studies revealed that treatment with Utt-B resulted in the induction of damage associated molecular patterns such as, ROS, HSP70 and inflammatory cytokines, IL-1{beta} and CXCL-10, suggesting the potential of Utt-B in triggering immunogenic cell death. Mechanistically, treatment with Utt-B enhances the antigen presentation potential, causes blockade of the major immune checkpoint molecules, namely, CTLA-4, PD-1, TIM-3, LAG-3 and TOX, and potentiates immunogenic apoptosis in the hepatic tumor microenvironment of mice pre-exposed to AFB1 via the activation of Zap70/Lck/GRZB signaling axis. Interestingly, it was also observed that Utt-B could abrogate the mutations induced by AFB1 in a concentration dependent manner. Taken together, the findings of the current study attest Utt-B as a propitious drug candidate against HCC.

cancer biology↗

bioRxiv2025

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.

cancer biology↗

bioRxiv2024

Uttroside B, a US-FDA-Designated Orphan Drug Against Hepatocellular Carcinoma (HCC), Impedes Non-alcoholic Steatohepatitis (NASH) and NASH -Induced HCC

IntroductionNon-alcoholic steatohepatitis (NASH) is characterized by excessive accumulation of fat, accompanied by inflammation and liver injury. NASH can lead to chronic conditions like fibrosis and cirrhosis, and has an elevated risk of progressing to hepatocellular carcinoma (HCC). Currently there are no FDA-approved drugs for the treatment of NASH. ObjectivesOur discovery of Uttroside B (Utt-B), a phytosaponin isolated from Solanum nigrum Linn., which exhibits remarkable anti-HCC potential, has gained global recognition and is currently a US-FDA-designated orphan drug against HCC. The present study highlights Utt-B as an anti-NASH molecule, by utilizing a High-Fat-Diet murine model, and as an inhibitor to the progression of NASH to HCC, using a streptozotocin-induced steatohepatitis-derived HCC animal model, thereby warranting its further validation as a propitious candidate drug molecule against NASH and NASH-induced HCC. MethodsHigh fat diet-induced NASH and streptozotocin-induced steatohepatitis-derived HCC were developed in C57BL/6 mice. Utt-B was administered intraperitoneally. q-PCR, immunoblotting and staining techniques such as Haematoxylin and eosin, Oil Red O, Sirius Red and Massons Trichrome, were performed to assess the therapeutic potency of Utt-B against NASH. Nanostring n-Counter analysis was conducted to verify the anti-fibrotic potential of Utt-B in NASH-induced HCC mouse model. ResultsUtt-B ameliorates the pathological features such as, steatosis, hepatocyte ballooning and inflammation associated with NASH. Utt-B up-regulates the expression of autophagy markers ATG7, Beclin-1 and LC-III and down-regulates the expression of -SMA, the indicator protein for the activation of hepatic stellate cells. Utt-B hinders the development of fibrosis and halts the progression of NASH to HCC in NASH-induced HCC mouse model. ConclusionOur investigation reveals that Utt-B effectively alleviates NASH and abrogates its progression to HCC. As no treatment options are currently available against NASH, our findings are very relevant and strengthen the prospect of developing Utt-B as a potent drug for the treatment of NASH and NASH-induced HCC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/622394v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1d637dcorg.highwire.dtl.DTLVardef@ed6b34org.highwire.dtl.DTLVardef@1195acaorg.highwire.dtl.DTLVardef@197b072_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

PD-1 endocytosis unleashes the cytolytic potential of check-point blockade in tumor immunity

PD-1 immune checkpoint blockade (ICB) is now a promising first-line treatment for many cancers. While the steric blockade of PD-1 binding to its ligand plays a role, the role of internalisation in promoting the efficacy of ICB has not been explored. In this study, we show that PD-1 internalisation also contributes by unlocking the full cytolytic potential of ICB in cancer immunotherapy. We found that anti-mouse and human PD-1 downregulate a subset of PD-1 surface receptors on T-cells with high-density surface PD-1 leaving T-cells with intermediate expression resistant to further internalisation. Down regulation was seen on both CD4 and CD8 cells but was maximally effective on CD8 effector cells. In human T-cells, nivolumab outperformed pembrolizumab in terms of rate and efficacy. We also found that PD-1 internalisation depended on bivalent antibody (Ab)-induced crosslinking, while monovalent Ab sterically blocked PD-1 without inducing endocytosis. Immunologically, while both monovalent and bivalent Ab limited B16-PD-L1 tumor growth, bivalent Ab was significantly more effective. In molecular terms, while both antibodies increased granzyme B (GZMB) expression in CD8+ cytolytic T-cells, the induction of the second key cytolytic pore-forming mediator, perforin, was dependent on the blockade and internalisation mediated by bilavent anti-PD-1. Our findings unveil a novel mechanism in checkpoint blockade where steric blockade combined with the removal of PD-1 from the cell surface by endocytosis can complement and optimize therapy. The targeting of PD-1 internalisation holds promise for enhancing anti-tumor immunity and improving PD-1 checkpoint blockade therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/591549v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1cbb458org.highwire.dtl.DTLVardef@ad15eborg.highwire.dtl.DTLVardef@17a2bf6org.highwire.dtl.DTLVardef@1dc5ba0_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefBen Saad et al define the mechanism of PD-1 inhibitory endocytosis and show that the removal of surface PD-1 by endocytosis plays a role in complementing and optimizing checkpoint blockade. Targeting PD-1 internalisation holds promise for enhancing anti-tumor immunity and improving the efficacy of PD-1 checkpoint blockade therapy.

immunology↗

bioRxiv2022

Augmented efficacy of uttroside B over sorafenib in a murine model of human hepatocellular carcinoma

BackgroundWe previously reported the potency of S. nigrum-derived uttroside B (Utt-B). Recently Utt-B is flagged as an orphan drug against hepatocellular carcinoma (HCC) by the US FDA. The current study aims to validate the enhanced in vivo efficacy of Utt-B over sorafenib, the first-line treatment option against HCC. MethodsHuman liver cancer cell line, HepG2 was employed as an HCC model and the comparison between Utt-B vs sorafenib therapeutic efficacies against HCC in vivo were evaluated in NOD.CB17-Prkdcscid/J mice that bear HepG2-induced HCC xenografts. ResultsOur data indicate that Utt-B is a more potent anti-HCC drug than sorafenib, in vivo. Apart from the superior therapeutic benefit over sorafenib, Utt-B is pharmacologically safer in vivo, and owing to this virtue, the drug-induced side effects are largely alleviated in the context of HCC chemotherapy. ConclusionsOur data demonstrate the superior therapeutic index of Utt-B over sorafenib against HCC. Clinical studies in HCC patients utilizing Utt-B, which now holds the US FDA approval as an orphan drug, is an essential step to promote this drug from bench to bedside.

cancer biology↗