Effects and mechanisms of betulinic acid on improving EGFR TKI‐resistance of lung cancer cells

Abstract

Epidermal growth factor receptor (EGFR) mutations have been identified in approximately 55% of lung cancer patients in Taiwan. Gefitinib (Iressa) and Erlotinib (Tarceva) are the first-generation targeting drugs to patients with EGFR gene mutants a work by inhibiting tyrosine kinase activity. However, resistance in EGFR-mutated patients to first-generation tyrosine kinase inhibitor (TKI) therapy after 8-11 months of treatment has occurred. Betulinic acid (BetA) is a pentacyclic triterpenoid natural product derived from widespread plants. BetA has been reported to have a cytotoxic effect in several cancers. The purpose of this study is to investigate the effects and mechanisms of BetA on dampening EGFR TKI-resistance of lung cancer cells. Our study has demonstrated by MTT assay that combining BetA and an EGFR TKI increased the cytotoxicity against EGFR TKI-resistance lung cancer cells. Based on flow cytometry, combination treatments of BetA with an EGFR TKI enhanced Sub-G1 accumulation, induced apoptosis and induced mitochondrial membrane potential loss. Using western blotting, BetA and EGFR TKI combined treatments inhibited cell cycle related protein and triggered apoptosis- and autophagy- related protein expression. Taken together, our data suggests that a target therapy combining BetA with an EGFR TKI improves drug efficacy in EGFR TKI-resistant lung cancer cells.

Additive Interactions between Betulinic Acid and Two Taxanes in In Vitro Tests against Four Human Malignant Melanoma Cell Lines

“…The study showed that the combination of BA and TKIs increased cell death in HCC827 and H1975 lung cancer cell lines by increasing the expression of apoptotic proteins and autophagy. Combination therapy with these compounds improved the effectiveness of anti-cancer therapy and reduced the side effects of chemotherapeutic agents [ 41 ].…”

Mapping Pharmacological Network of Multi-Targeting Litchi Ingredients in Cancer Therapeutics

“…breast and lung cancer (Ko et al, 2018;Cai et al, 2018;Wang et al, 2019c) inhibiting metabolism CAV1, IKBA, LDHA/B, MYC, PDK1, RELA breast cancer (Jiao et al, 2019;Zeng et al, 2019) suppressing stemness NANOG, OCT4, PRKAA2, SOX2 pancreatic cancer (Sun et al, 2019) b-Sitosterol promoting apoptosis BAX, BCL2, CASP3 gastric cancer (Zhao et al, 2009) sensitizing chemotherapy AKT1, GSK3B, RELA, BAX, BCL2, SNAIL1, VIM pancreatic cancer (Cao et al, 2018) Triterpenes Lupeol anti-proliferation AKT1, BCL2, CCNA2/B/D3, CDC2/ 26C, CDK2/N1A/N1B/N2A, CLAUDIN1, CTNNB1, MAPK1, MYC, PLK1, TCF4, TP53…”

Betülinik Asit ve Antikanser Etkileri

“…Akciğer adenokarsinoma hücre soylarında yapılan diğer bir çalışmada, akciğer kanserinde sıklıkla mutasyonu gözlenen endoteliyal büyüme faktörü reseptörünün (EGFR) tirozin kinaz inhibitörleri (TKI) Gefitinib ve Erlotinib'e dirençli H1975 ve EGFR mutant TKI duyarlı HCC827 hücre soylarında betülinik asidin, EGFR-TKI ile kombine tedavisi sonucu H1975 hücrelerinin canlılığını azalttığı, apoptotik hücre oranını arttırdığı ve hücre döngüsü ilişkili proteinlerin ekspresyonunu azalttığı gözlemlenmiştir. Ek olarak, otofaji ilişkili proteinlerin ekspresyonlarını arttırıp mitokondri membran potansiyelinin kaybına yol açmıştır (30). Son yıllarda ilaç etkinliğinin iyileştirilmesinde nanopartükül teknolojisi sıklıkla kullanılmaktadır.…”