Abstract
Non-small-cell lung cancer (NSCLC) accounts for most lung cancer cases. Therapeutic interventions integrating the use of different agents that focus on different targets are needed to overcome this set of diseases. The proteasome system has been demonstrated clinically as a potent therapeutic target for haematological cancers. However, promising preclinical data in solid tumors are yet to be confirmed in clinics. Herein, the combinational use of Bortezomib (BZM) and 2-aminoethoxydiphenylborane (2-APB) toward NSCLC cells was studied. We confirmed that BZM-triggered cytoprotective autophagy that may counteract with the cytotoxic effects of the drug per se. 2-APB was selected from screening of a commercial natural compounds library, which potentiated BZM-induced cytotoxicity. Such an enhancement effect was associated with 2-APB-mediated autophagy inhibition. In addition, we revealed that 2-APB suppressed calcium-induced autophagy in H1975 and A549 NSCLC cells. Interestingly, BZM [0.3 mg/kg/3 days] combined with 2-APB [2 mg/kg/day] significantly inhibited both primary (around 47% tumor growth) and metastatic Lewis lung carcinoma after a 20-day treatment. Our results suggested that BZM and 2-APB combination therapy can potentially be developed as a novel formulation for lung cancer treatment.
Highlights
Lung cancer remains the leading cause of cancer deaths globally[1], whereas non-small-cell lung cancer (NSCLC) is the most common type accounting for 85% of all lung cancers
The immunoblotting images showed an increasing LC3phosphatidylethanolamine conjugate (LC3-II) expression in both NSCLC cell lines reaching the maximum level after 24 h, demonstrating that BZM-induced autophagy (Fig. 1c, d)
In the present study, we confirmed that BZM therapy can trigger autophagy which may protect cancer cells from BZM-induced cell death
Summary
Lung cancer remains the leading cause of cancer deaths globally[1], whereas non-small-cell lung cancer (NSCLC) is the most common type accounting for 85% of all lung cancers. The poor in vivo efficacy as observed in BZM-treated solid tumors may be mediated by the activation of autophagy pathway that functions as an alternative mechanism of protein degradation assisting cancer cell survival via the relief in proteotoxic stress[10,11,12,13,14,15,16]. BZM causes the accumulation of misfolded and ubiquitinated proteins that eventually lead to endoplasmic reticulum (ER) stress and increase intracellular calcium (Ca2+) release that activates autophagy[16,17,18,19,20,21,22]. Preclinical trials have shown that HCQ in combination therapy leads to enhancement of antineoplastic effects in different cancer models, including BZM for myeloma. HCQ displays reduced potency in vivo, creating a demand for the production of more potent autophagy inhibitors[25]
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