Biology subjects

Swetha, M.

Publications and source records attributed to Swetha, M..

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↗

bioRxiv2023

Kaempferide induces apoptosis in cervical cancer by attenuating the HPV oncoproteins, E6 and E7

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/541414v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1e1cf7forg.highwire.dtl.DTLVardef@1fdc5dforg.highwire.dtl.DTLVardef@1c9baa6org.highwire.dtl.DTLVardef@fcf063_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO A schematic diagram depicting the anti-cancer potential of kaempferide against cervical cancer and its probable mechanism of action. C_FIG Despite the advancement in HPV prevention strategies, cervical cancer is a leading cause of cancer death in women worldwide. The anticancer potential of kaempferide, which was derived from Chromolaena odorata, was previously revealed in our in-vitro study. The current investigation aims to confirm the therapeutic efficacy of the molecule against cervical cancer, in-vitro and in-vivo. In NOD-SCID mice with HeLa Luc+ xenografts, kaempferide significantly increases ROS production resulting in a drastic decrease in the luc activity and growth of cervical tumours. It also exhibits down-regulation of oncoproteins E6, E7 and MDM2 and concurrent up-regulation of p53, p21 and pRb. The degradation of phospho-pRb, along with a strong expression of cleaved PARP, TUNEL positivity and a significant decrease in PCNA expression, confirms apoptotic mode of cell death in the treated tissues. Taken together, our study reveals the antioncogenic potential of kaempferide, which regulates oncoproteins and tumor suppressors accordingly. This is the first report depicting kaempferide as an inhibitor of HPV oncoproteins and hence as a candidate drug molecule against cervical cancer.

cancer biology↗

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↗