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PP-38

An Asteraceae medicinal plant-derived active pharmaceutical ingredients

inhibit melanoma lung metastasis through reprograming tumor

microenvironment and metabolism

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Chung-Chih Yang, Meng-Ting Chang, Pei-Wen Hsiao, Lie-Fen Shyur* ,1

1 Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115201, Taiwan
* E-mail: lfshyur@ccvax.sinica.edu.tw

Abstract
Melanoma is the most aggressive form of skin cancer, with approximately 50% of cases
harboring BRAF mutations, contributing to high metastatic potential and poor prognosis. BRAF
inhibitors, such as vemurafenib (PLX4032), are used in late-stage melanoma; however,
acquired resistance and adverse effects limit their efficacy. This study identified active
pharmaceutical ingredients (API) from a medicinal Asteraceae plant (designated BC) using a
bioactivity-guided approach which shows potent anti-metastatic effects on melanoma lung
metastasis. In a high-propensity lung metastatic A375LM eIF4g/Luc xenograft mouse model,
treatment with PLX4032 (50 mg/kg) and BC_API (20 mg/kg) suppressed lung metastases and
extended animal survival to 40 and 34 days, respectively, compared to 26 days in control mice.
The BC_API also effectively inhibited orthotopic B16 melanoma growth in syngeneic mice.
The tumor microenvironment abundant with M2 macrophages in nests and invasive fronts of
the tumor group were shifted toward M1 after BC_API treatment by increasing M1/M2 ratio.
In vitro studies showed BC_API inhibited the epithelial-mesenchymal transition phenotype,
reduced cancer stem-like characteristics, and induced apoptosis in melanoma cells. Furthermore,
BC_API promoted M1 macrophage polarization and its phagocytic ability in vitro and ex vivo.
GC/MS and LC/MS-based metabolomics and KEGG-database pathway analysis showed that
BC_API affected primary or lipid metabolism in tumor-bearing mice, such as unsaturated fatty
acid/oxylipin metabolism or biosynthesis and arginine biosynthesis that might be associated
with melanoma invasion/metastasis that contribute to the anti-tumor growth or metastasis effect
of the BC_API. This study highlights the great potential of a phytoAPI as botanical drug
candidate for metastatic melanoma therapy.

Keywords: Metastatic melanoma; Tumor microenvironment; Macrophage polarization;
Primary metabolism; Asteraceae plant