Tag Archives: Sorafenib

Hepatocellular carcinoma

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Hedgehog signaling mastery: R51211’s promise in augmenting the
therapeutic efficacy of sorafenib

By A. M. Hasan, Simona Cavalu, Sameh Saber et al.

The role of hedgehog signaling in sorafenib resistance has been also examined in HCC. R51211, known as itraconazole, has been safely employed in clinical practice. Through in vitro and in vivo investigations, we assessed the potential of R51211 to enhance the therapeutic efficacy of sorafenib by inhibiting the hedgehog signaling. This dual therapy exhibited an increased capacity to induce apoptosis, as evidenced by alterations in the Bax/BCL-2 ratio and caspase-3, along with a propensity to promote autophagy, as indicated by changes in BECN1, p62, and the LC3I/LC3II ratio. Furthermore, the combination therapy resulted in significant reductions in biomarkers associated with liver preneoplastic alterations, improved liver microstructure, and mitigated changes in liver function enzymes. Copyright Simona Cavalu et al.

Effect of R51211 on HepG2 cell proliferation (A), Huh-7 cell proliferation (B), LDH leakage (C), and intracellular ROS production (D). Copyright Simona Cavalu et al.
Effect of R51211 on the mRNA expression of SMO (A), SMO protein
expression level (B), the mRNA expression of GLI1 (C), GLI1 protein expression
level (D), the mRNA expression of GLI2 (E), and GLI2 protein expression level
(F). Copyright Simona Cavalu et al.
Dose-response matrix for HepG2 cells treated with R51211 and sorafenib in the presence of SAG. Copyright Simona Cavalu et al.

Sorafenib stands as a standard therapy for advanced-stage HCC patients. Despite its widespread use, the therapeutic efficacy of sorafenib is hindered by drug resistance, thereby constraining the number of patients who can derive substantial benefits from this treatment. In the present study, our findings, for the first time revealed the capacity of R51211 to increase the sensitivity of HepG2 cells to the effects of sorafenib as revealed by calculating the synergy scores for R51211 and sorafenib combinations in the absence of the hedgehog activator SAG. Our findings revealed that the use of SAG counteracted the synergistic antiproliferative potential of R51211 with sorafenib in HepG2 cells. Consequently, it can be inferred that the synergistic potential of R51211 with sorafenib is likely mediated through hedgehog inhibition, and the introduction of SAG has a modulating effect on this synergy. Copyright Simona Cavalu et al.

The primary outcome of this study demonstrates the successful augmentation of sorafenib’s therapeutic effectiveness by R51211 in both HepG2 cells and rats subjected to DENA treatment. Nevertheless, additional preclinical investigations are essential to validate the therapeutic potential of the R51211 and sorafenib combination in impeding the progression of liver cancer. Furthermore, it is imperative to explore resistant in vitro and in vivo models of hepatocarcinogenesis to evaluate the capability of
R51211 in overcoming resistance to sorafenib treatment.

Copyright Simona Cavalu et al.

Full text here https://doi.org/10.1016/j.lfs.2024.122791

Ganetespib (STA-9090) augments sorafenib efficacy via necroptosis induction in hepatocellular carcinoma: Implications from preclinical data for a novel therapeutic approach

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By Sameh Saber, Alexandru Hasan, Simona Cavalu et al.

Sorafenib, a multikinase inhibitor, is a first-line treatment for advanced hepatocellular carcinoma, but its longterm effectiveness is limited by the emergence of resistance mechanisms. HSP90 plays a critical role in conferring resistance to sorafenib in HepG2 cells under hypoxic
conditions and N-Nitrosodiethylamine-exposed mice. To augment the effects of sorafenib, we investigated the use of ganetespib, an HSP90 inhibitor. We observed a significant negative correlation between LAMP2 and MLKL. Combining ganetespib with sorafenib showed a synergistic cytotoxic effect and resulted in the accumulation of p62 and inhibition of macroautophagy. Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.

Effect of SFB and GTSB on % growth inhibition (A)
and combination index (B). The CTC50 values represent the
concentration at which 50% of cell growth is inhibited and
providing insights into the drugs’ potency against the
tested cells. Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.
Effect of SFB and the combination of GTSB and SFB on the levels of HSP90 (A), HSP70 (B), LAMP2 (C), MLKL (D), and p62 (E) in HepG2 cells. Additionally, a
correlation analysis of the measured parameters was conducted (F). Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.
Effect of SFB and the combination of GTSB and SFB on the number of
nodules per liver (A), liver index (B), AFP (C), and ROS (D). Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.
Liver specimens were stained with H&E to evaluate the effect of different treatments on hepatic architecture and the development of hepatocellular carcinoma. These findings suggest that SFB and the combination of SFB with GTSB may have therapeutic potential for treating HCC. Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.
Correlation analysis for the effect of SFB and the combination of GTSB and SFB on the measured parameters (HSP90, HSP70, LAMP2, MLKL, p62, HIF-1α,
and VEGF).Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.

The proper transportation of proteins across the lysosomal membrane
in the CMA process is dependent on essential components,
including HSP90 and LAMP2. Our study indicates that under hypoxic
conditions, there is a significant upregulation of HSP90 and LAMP2
expression. Our findings suggest that MLKL, which is the mediator of
necroptosis, can be degraded through the CMA pathway under hypoxia.
Furthermore, our preclinical data show that HSP90 plays a critical role
in conferring resistance to SFB under hypoxia by inhibiting necroptosis.
Combining GTSB with SFB may offer a promising therapy for HCC. Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.

Full text available at: https://doi.org/10.1016/j.biopha.2023.114918