Paris polyphylla enhances the anti-metastatic efficacy of maimendong decoction against lung cancer.

Abstract

BACKGROUND: Maimendong decoction (MMDD), a classic traditional Chinese medicine (TCM) formula prescribed for ‘lung atrophy’, has demonstrated efficacy against various pulmonary disorders. Our prior research confirmed that MMDD inhibit lung cancer metastasis by modulating natural killer (NK) cells. Paris polyphylla (P.P), a TCM herb with known anti-tumor properties, is often incorporated into classic formulas to enhance therapeutic outcomes. This study aimed to boost the anti-metastatic efficacy of MMDD against lung cancer by incorporating Paris polyphylla (Chonglou) and to investigate the underlying mechanisms. METHODS: The Modified Maimendong Decoction (MMDD + P.P) Was Prepared by Adding 9–18 g of Paris polyphylla. Its Effects on the proliferation, migration, and Apoptosis of CTC-TJH-01 and LLC Cells Were Assessed Using CCK-8, Transwell, and Annexin V-FITC/PI Flow Cytometry assays. Apoptosis-related Proteins Were Analyzed by Western blot. A Tail Vein injection-induced Lung Metastasis Model in C57BL/6 Mice Was Established To Evaluate the Effects of MMDD + P.P, both Alone and in Combination with an anti-PD-1 antibody, on Metastasis Flow cytometry was used to profile T cell and NK cell populations in peripheral blood. Histological and molecular analyses of metastatic tissues were performed using H&E staining, immunohistochemistry (for Ki-67 and cleaved caspase-3), and immunofluorescence (for CD8+ T cell and NK cell infiltration). RESULTS: Compared to MMDD alone, MMDD + P.P (18 g) significantly inhibited proliferation and migration, and induced apoptosis in both CTC-TJH-01 and LLC cells. These effects were associated with the upregulation of pro-apoptotic proteins (cleaved caspase-3, BAX, cleaved PARP) and downregulation of anti-apoptotic proteins (BCL-2, Survivin). In vivo, while both MMDD and MMDD + P.P reduced the number of lung metastatic nodules, MMDD + P.P (18 g) was uniquely effective in significantly reducing overall tumor burden, which correlated with decreased Ki-67 and increased cleaved caspase-3 in metastatic foci. Furthermore, MMDD + P.P (18 g) significantly increased the proportions and tumor-infiltration of NK cells and CD8+ T cells. It also synergized with anti-PD-1 therapy, enhancing its anti-metastatic effect and boosting the expression of cytotoxic markers (CD107a, perforin, granzyme B) and TNF-α in CD8+ T cells. CONCLUSION: Incorporating Paris polyphylla into MMDD enhances its anti-metastatic efficacy through a dual mechanism: directly inducing apoptosis in lung cancer cells and amplifying anti-tumor immunity by increasing the abundance and cytotoxic function of CD8+ T cells. The synergy between MMDD + P.P and anti-PD-1 antibody therapy highlights the potential of this modified TCM formula as a promising adjunctive treatment for inhibiting lung cancer metastasis.