Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma

Swamy, Supritha G.; Kameshwar, Vivek H.; Shubha, Priya Babu; Looi, Chung Yeng; Shanmugam, Muthu K.; Arfuso, Frank; Sethi, Gautam; Swamy, S. Nanjunda; Bishayee, Anupam

doi:10.1007/s11523-016-0452-7

Cited by 94 publications

(64 citation statements)

References 107 publications

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“…The signal transducer and activator of transcription 3 (STAT3) pathway is one of the major signaling pathways that promote tumor progression in HCC (8). This pathway is stimulated by inflammatory cytokines and growth factors (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of protein disulfide‑isomerase A3 expression inhibits cell proliferation and induces apoptosis through STAT3 signaling in hepatocellular carcinoma

et al. 2019

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Protein disulfide-isomerase A3 (PDIA3) is a chaperone protein that modulates folding of newly synthesized glycoproteins and responds to endoplasmic reticulum (ER) stress. Previous studies reported that increased expression of PDIA3 in hepatocellular carcinoma (HCC) is a marker for poor prognosis. However, the mechanism remains poorly understood. The aim of the present study, therefore, was to understand the role of PDIA3 in HCC development. First, immunohistochemical staining of tissues from 53 HCC cases revealed that HCC tissues with high PDIA3 expression exhibited a higher proliferation index and contained fewer apoptotic cells than those with low expression. In addition, the knockdown of PDIA3 significantly inhibited cell proliferation and induced apoptosis in HCC cell lines. These results suggest that PDIA3 regulates cell proliferation and apoptosis in HCC. An examination of whether PDIA3 knockdown induced apoptosis through ER stress revealed that PDIA3 knockdown did not increase ER stress marker, 78 kDa glucose-regulated protein, in HCC cell lines. Furthermore, the association between PDIA3 and the signal transducer and activator of transcription 3 (STAT3) signaling pathway were investigated in vitro and in vivo. Immunofluorescence staining and co-immunoprecipitation experiments revealed colocalization and binding, respectively, of PDIA3 and STAT3 in HCC cell lines. The knockdown of PDIA3 decreased the levels of phosphorylated STAT3 (P-STAT3; Tyr705) and downstream proteins of the STAT3 signaling pathway: The anti-apoptotic proteins (Bcl-2-like protein 1, induced myeloid leukemia cell differentiation protein Mcl-1, survivin and X-linked inhibitor of apoptosis protein). In addition, PDIA3 knockdown provided little inhibitory effect on cell proliferation in HCC cell lines treated with AG490, a tyrosine-protein kinase JAK/STAT3 signaling inhibitor. Finally, an association was demonstrated between PDIA3 and P-STAT3 expression following immunostaining of 35 HCC samples. Together, the present data suggest that PDIA3 promotes HCC progression through the STAT3 signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Downregulation of protein disulfide‑isomerase A3 expression inhibits cell proliferation and induces apoptosis through STAT3 signaling in hepatocellular carcinoma

et al. 2019

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“…Sorafenib tosylate (SFN), a tyrosine kinase inhibitor, has emerged as a potent orally bioavailable antineoplastic agent (Swamy et al, ), particularly for hepatocellular carcinoma, renal carcinoma and thyroid cancer. Chemically, SFN is 4‐[4‐[[4‐chloro‐3‐(trifluoromethyl)phenyl]carbamoylamino]phenoxy]‐N‐methylpyridine‐2‐carboxamide;4‐methylbenzenesulfonic acid (Figure ; https://pubchem.ncbi.nlm.nih.gov).…”

Section: Introductionmentioning

confidence: 99%

Development of a validated liquid chromatographic method for quantification of sorafenib tosylate in the presence of stress‐induced degradation products and in biological matrix employing analytical quality by design approach

Sharma

Khurana

Jain

et al. 2018

Biomedical Chromatography

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The current research work envisages an analytical quality by design-enabled development of a simple, rapid, sensitive, specific, robust and cost-effective stability-indicating reversed-phase high-performance liquid chromatographic method for determining stress-induced forced-degradation products of sorafenib tosylate (SFN). An Ishikawa fishbone diagram was constructed to embark upon analytical target profile and critical analytical attributes, i.e. peak area, theoretical plates, retention time and peak tailing. Factor screening using Taguchi orthogonal arrays and quality risk assessment studies carried out using failure mode effect analysis aided the selection of critical method parameters, i.e. mobile phase ratio and flow rate potentially affecting the chosen critical analytical attributes. Systematic optimization using response surface methodology of the chosen critical method parameters was carried out employing a two-factor-three-level-13-run, face-centered cubic design. A method operable design region was earmarked providing optimum method performance using numerical and graphical optimization. The optimum method employed a mobile phase composition consisting of acetonitrile and water (containing orthophosphoric acid, pH 4.1) at 65:35 v/v at a flow rate of 0.8 mL/min with UV detection at 265 nm using a C column. Response surface methodology validation studies confirmed good efficiency and sensitivity of the developed method for analysis of SFN in mobile phase as well as in human plasma matrix. The forced degradation studies were conducted under different recommended stress conditions as per ICH Q1A (R2). Mass spectroscopy studies showed that SFN degrades in strongly acidic, alkaline and oxidative hydrolytic conditions at elevated temperature, while the drug was per se found to be photostable. Oxidative hydrolysis using 30% H O showed maximum degradation with products at retention times of 3.35, 3.65, 4.20 and 5.67 min. The absence of any significant change in the retention time of SFN and degradation products, formed under different stress conditions, ratified selectivity and specificity of the systematically developed method.

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“…2 It is approved for the management of unresectable hepatocellular carcinoma. It acts by inhibiting tyrosine kinase receptors such as vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) and epidermal growth factor (EGF).…”

Section: Discussionmentioning

confidence: 99%

Sorafenib induced pustular psoriasis in a patient of hepatocellular carcinoma: a rare case report

Sharma

Bassi

Kaur³

2018

Int J Res Dermatol

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<p class="abstract">Pustular psoriasis is the least common form of psoriasis characterized by the formation of psoriatic plaques studded with pustules. Sorafenib is an oral multi-targeted kinase inhibitor approved for the management of hepatocellular carcinoma. We report a biopsy proven case of pustular psoriasis induced by Sorafenib in a patient of hepatocelluar carcinoma. Cutaneous adverse effects with Sorafenib are rare but are not life threatening. We are reporting this case because of the rarity of association and for highlighting the need for early detection and management.</p>

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Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma

Cited by 94 publications

References 107 publications

Downregulation of protein disulfide‑isomerase A3 expression inhibits cell proliferation and induces apoptosis through STAT3 signaling in hepatocellular carcinoma

Downregulation of protein disulfide‑isomerase A3 expression inhibits cell proliferation and induces apoptosis through STAT3 signaling in hepatocellular carcinoma

Development of a validated liquid chromatographic method for quantification of sorafenib tosylate in the presence of stress‐induced degradation products and in biological matrix employing analytical quality by design approach

Sorafenib induced pustular psoriasis in a patient of hepatocellular carcinoma: a rare case report

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