Polyphyllin I Overcomes EMT-Associated Resistance to Erlotinib in Lung Cancer Cells <i>via</i> IL-6/STAT3 Pathway Inhibition

Abstract

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is the most important limiting factor for treatment efficiency in EGFR-mutant non-small cell lung cancer (NSCLC). Much work has linked the epithelial-mesenchymal transition (EMT) to the emergence of drug resistance, consequently, ongoing research has been focused on exploring the therapeutic options to reverse EMT for delaying or preventing drug resistance. Polyphyllin I (PPI) is a natural compound isolated from Paris polyphylla rhizomes and displayed anti-cancer properties. In the current work, we aimed to testify whether PPI could reverse EMT and overcome acquired EGFR-TKI resistance. We exposed HCC827 lung adenocarcinoma cells to erlotinib which resulted in acquired resistance with strong features of EMT. PPI effectively restored drug sensitivity of cells that obtained acquired resistance. PPI reversed EMT and decreased interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway activation in erlotinib-resistant cells. Moreover, addition of IL-6 partially abolished the sensitization response of PPI. Furthermore, co-treatment of erlotinib and PPI completed abrogation of tumor growth in xenografts, which was associated with EMT reversal. In conclusion, PPI serves as a novel solution to conquer the EGFR-TKI resistance of NSCLC via reversing EMT by modulating IL-6/STAT3 signaling pathway. Combined PPI and erlotinib treatment provides a promising future for lung cancer patients to strengthen drug response and prolong survival.

Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

“…This enhanced the effect of erlotinib on lung tumor growth both in vitro and in vivo. Thus, combined PPI and erlotinib strengthened drug response and provided a novel therapeutic for patients with lung cancer [57]. Our findings suggested that PPI sensitized or enhanced the effect of enzalutamide on controlling CRPC cell growth or vice versa by targeting p65, HOTAIR, and MUC1 regulatory signaling axis, implying a potential synergy between PPI and enzalutamide in anti-androgen-resistant ways.…”

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

“…In addition, polyphyllin I, a steroidal saponin derived from Paris polyphylla , has shown anti inflammatory and anticancer properties. It was suggested that polyphyllin I, which reversed EMT by modulating the IL‐6/STAT3 pathway, served as a novel solution to conquer EGFR‐TKI resistance in non–small‐cell lung cancer (Figure ). Therefore, combined treatment with polyphyllin I and erlotinib is a promising therapy for lung cancer patients to strengthen drug efficacy and reduce drug resistance .…”

“…It was suggested that polyphyllin I, which reversed EMT by modulating the IL‐6/STAT3 pathway, served as a novel solution to conquer EGFR‐TKI resistance in non–small‐cell lung cancer (Figure ). Therefore, combined treatment with polyphyllin I and erlotinib is a promising therapy for lung cancer patients to strengthen drug efficacy and reduce drug resistance . The other compound, quercetin, is a flavonoid widely distributed in fruits, vegetables, and beverages that shows antioxidative, anti inflammatory, and anticancer properties.…”

Molecular cross‐talk of IL‐6 in tumors and new progress in combined therapy

“…It possesses anti‐cancer activities and can reverse EMT by blocking the IL6/STAT3 pathway to overcome NSCLC cell resistance to EGFR‐TKIs. The combined use of PPI and erlotinib can possibly reverse the acquired resistance to EGFR‐TKIs and prolong patient life …”