Synergistic antitumor activity of sorafenib and the NUPR1 inhibitor LZX-2-73 in multiple cancer models

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Combination therapy is crucial for overcoming cancer drug resistance and enhancing treatment efficacy.
• Sorafenib is an FDA-approved multi-targeted kinase inhibitor with broad anticancer activity but limited combination therapies.
• Nuclear protein 1 (NUPR1) is an emerging target in cancer therapy.

Purpose of the Study:

• To investigate the synergistic anticancer effects of combining the NUPR1 inhibitor LZX-2-73 with sorafenib.
• To evaluate the underlying mechanisms of this combination therapy, including oxidative stress induction and cell death pathways.
• To assess the efficacy of the LZX-2-73 and sorafenib combination in preclinical cancer models.

Main Methods:

• In vitro studies using various cancer cell lines and primary pancreatic ductal adenocarcinoma (PDAC) organoids.
• Assessment of cell death markers, including lactate dehydrogenase (LDH) release and caspase 3/7 activity.
• Measurement of oxidative stress markers such as reactive oxygen species (ROS), glutathione ratio, malondialdehyde (MDA), and lipid hydroperoxides.
• In vivo studies using a pancreatic cancer xenograft mouse model.

Main Results:

• The combination of LZX-2-73 and sorafenib demonstrated significant synergistic anticancer effects in vitro and in vivo.
• This combination markedly induced cancer cell death through massive oxidative stress, evidenced by increased LDH release, caspase activity, ROS accumulation, and MDA levels.
• Tumor growth was effectively inhibited in the pancreatic cancer xenograft mouse model treated with the combination therapy.

Conclusions:

• The combination of the NUPR1 inhibitor LZX-2-73 with sorafenib offers a promising new strategy for enhancing anticancer activity.
• This combination therapy effectively induces cancer cell death via oxidative stress and shows potent tumor growth inhibition.
• This study opens new avenues for developing novel combination therapies targeting NUPR1 and utilizing sorafenib for expanded cancer treatment indications.