Combination Treatment With Inhibitors of ERK and Autophagy Enhances Antitumor Activity of Betulinic Acid in Non–small-Cell Lung Cancer In Vivo and In Vitro
| Autor: | Hui-Yun Wang, Qian-Nan Ren, Di Cao, Shi-Juan Mai, Ningning Zhou, Bing Feng, Chao-Yue Sun, Shanshan Zhang |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway autophagy RM1-950 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine betulinic acid Betulinic acid medicine Pharmacology (medical) Protein kinase B combination Pharmacology Cell growth Kinase Autophagy apoptosis Cancer medicine.disease lung cancer ERK 030104 developmental biology chemistry 030220 oncology & carcinogenesis Cancer cell Cancer research Therapeutics. Pharmacology |
| Zdroj: | Frontiers in Pharmacology, Vol 12 (2021) |
| ISSN: | 1663-9812 |
| Popis: | Aberrant activation of the Ras–ERK signaling pathway drives many important cancer phenotypes, and several inhibitors targeting such pathways are under investigation and/or approved by the FDA as single- or multi-agent therapy for patients with melanoma and non–small-cell lung cancer (NSCLC). Here, we show that betulinic acid (BA), a natural pentacyclic triterpenoid, inhibits cell proliferation, and induces apoptosis and protective autophagy in NSCLC cells. Thus, the cancer cell killing activity of BA is enhanced by autophagy inhibition. Mitogen-activated protein kinases, and especially ERK that facilitates cancer cell survival, are also activated by BA treatment. As such, in the presence of ERK inhibitors (ERKi), lung cancer cells are much more sensitive to BA. However, the dual treatment of BA and ERKi results in increased protective autophagy and AKT phosphorylation. Accordingly, inhibition of AKT has a highly synergistic anticancer effect with co-treatment of BA and ERKi. Notably, autophagy inhibition by hydroxychloroquine (HCQ) increases the response of lung cancer cells to BA in combination with ERKi. In vivo, the three-drug combination (BA, ERKi, and HCQ), resulted in superior therapeutic efficacy than single or dual treatments in the xenograft mouse model. Thus, our study provides a combined therapy strategy that is a highly effective treatment for patients with NSCLC. |
| Databáze: | OpenAIRE |
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