Title:Pharmacological Approaches in an Experimental Model of Non-Small Cell Lung Cancer: Effects on Tumor Biology
Volume: 22
Issue: 34
Author(s): Mercè Mateu-Jimenez, Clara Fermoselle, Federico Rojo, Javier Mateu, Raúl Peña, Alejandro J. Urtreger, Miriam J. Diament, Elisa D. Bal de Kier Joffé, Lara Pijuan, Antonio García de Herreros and Esther Barreiro
Affiliation:
Keywords:
Lung adenocarcinoma, therapeutic strategies, stromal structure, tumor proliferation, apoptosis, autophagy, redox imbalance,
inflammation.
Abstract: Lung cancer (LC) remains the leading cause of cancer mortality worldwide, and
non-small cell LC (NSCLC) represents 80% of all LC. Oxidative stress and inflammation,
autophagy, ubiquitin-proteasome system, nuclear factor (NF)-κB, and mitogen activated
protein kinases (MAPK) participate in LC pathophysiology. Currently available treatment
for LC is limited and in vivo models are lacking. We hypothesized that antioxidants and NF-
κB, MAPK, and proteasome inhibitors may exert an antitumoral response through attenuation
of several key biological mechanisms that promote tumorigenesis and cancer cell
growth. Body and tumor weights, oxidative stress, antioxidants, inflammation, NF-κB p65
expression, fibulins, apoptosis, autophagy, tumor and stroma histology were evaluated in the
subcutaneous tumor of LC (LP07 adenocarcinoma) BALB/c mice, with and without concomitant
treatment with NF-κB (sulfasalazine), MEK (U0126), and proteasome (bortezomib)
inhibitors, and N-acetyl cysteine (NAC). Compared to LC control mice, in subcutanous
tumors, the four pharmacological agents reduced oxidative stress markers and tumor proliferation (ki-67). Inflammation
and NF-κB p65 expression were attenuated by NF-κB and MAPK inhibitors, and the latter also enhanced
apoptotic markers. Catalase was induced by the three inhibitors, while bortezomib also promoted superoxide
dismutase expression. NF-κB and MEK inhibitors significantly reduced tumor burden through several biological
mechanisms that favored tumor degradation and attenuated tumor proliferation. These two pharmacological
agents may enhance the anti-tumor activity of selectively targeted therapeutic strategies for LC. Proteasomal
inhibition using bortezomib rather promotes tumor degradation, while treatment with antioxidants cannot be
recommended. This experimental model supports the use of adjuvant drugs for the improvement of LC treatment.
