Abstract
Non-small cell lung cancer (NSCLC) patients carrying an epidermal growth factor receptor (EGFR) mutation are initially sensitive to EGFR-tyrosine kinase inhibitors (TKIs) treatment, but soon develop an acquired resistance. The treatment effect of EGFR-TKIs-resistant NSCLC patients still faces challenges. Cucurbitacin B (CuB), a triterpene hydrocarbon compound isolated from plants of various families and genera, elicits anticancer effects in a variety of cancer types. However, whether CuB is a viable treatment option for gefitinib-resistant (GR) NSCLC remains unclear. Here, we investigated the anticancer effects and underlying mechanisms of CuB. We report that CuB inhibited the growth and invasion of GR NSCLC cells and induced apoptosis. The inhibitory effect of CuB occurred through its promotion of the lysosomal degradation of EGFR and the downregulation of the cancerous inhibitor of protein phosphatase 2A/protein phosphatase 2A/Akt (CIP2A/PP2A/Akt) signaling axis. CuB and cisplatin synergistically inhibited tumor growth. A xenograft tumor model indicated that CuB inhibited tumor growth in vivo. Immunohistochemistry results further demonstrated that CuB decreased EGFR and CIP2A levels in vivo. These findings suggested that CuB could suppress the growth and invasion of GR NSCLC cells by inducing the lysosomal degradation of EGFR and by downregulating the CIP2A/PP2A/Akt signaling axis. Thus, CuB may be a new drug candidate for the treatment of GR NSCLC.
Highlights
Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death
We further showed that Cucurbitacin B (CuB) caused the downregulation of epidermal growth factor receptor (EGFR) expression at the protein level (Figure 3A)
We reported that cancerous inhibitor of protein phosphatase 2A (CIP2A) plays an important role in the proliferation and aggressiveness of Non-small cell lung cancer (NSCLC) and the natural compound oridonin could downregulate CIP2A levels in GR NSCLC cells [20]
Summary
Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death. Most NSCLC patients initially respond to chemotherapy, they gradually become drug-resistant, which in turn leads to cancer recurrence and poor prognosis [3]. Molecules 2019, 24, 647 kinase inhibitors (EGFR-TKIs). The treatment effect of EGFR-TKIs is significant for NSCLC patients with EGFR activating mutations (such as exon 19 deletion and the L858R point mutation). Cancer cells often develop TKI resistance, which in turn causes tumor recurrence [4]. Patients with acquired resistance to gefitinib or erlotinib have acquired a second mutation in exon 20 of the EGFR gene, resulting in the replacement of threonine at position 790 in the protein kinase domain with methionine (T790M). Treatment strategies for secondary mutations of EGFR (T790M) should be developed to overcome EGFR-TKI resistance, which would benefit NSCLC patients
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