Page 329 - 2025中醫藥與天然藥物聯合學術研討會-中醫藥與天然藥物的挑戰Ｘ機遇與未來大會手冊

TC-14

A medicinal orchid plant-derived active pharmaceutical ingredients impede

vemurafenib-resistant melanoma

1
Mu-Fan Tsou, #,1,2 Chung-Hsing Chang, Lie-Fen Shyur* ,1,2

1 Doctoral Degree Program in Translational Medicine, Tzu Chi University and Academia
Sinica, Taiwan
2 Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
* E-mail: jaclyn@gate.sinica.edu.tw

Abstract
Melanoma, one of the most aggressive skin cancers, accounts about ~300,000 new cases and
60,000 deaths annually worldwide, and also ranks among the top ten cancers in Taiwan.
Approximately 50–60% of patients harbor BRAF mutations, ~90% of which are BRAF V600E .
Although vemurafenib (PLX4032), a BRAF V600E inhibitor approved by the U.S. FDA in 2011,
shows initial efficacy, nearly half of patients develop primary or acquired resistance. Moreover,
vemurafenib may induce adverse effects, such as keratoacanthomas arising from HRAS Q61L -
mutant keratinocytes. This study investigated the therapeutic potential of a traditional medicinal
orchid plant (designated OP), historically used to alleviate dermatological disorders on
inhibiting vemurafenib resistant melanoma. Bioactivity-guided fractionation of OP stem
extracts identified an active pharmaceutical ingredients (APIs) fraction, predominantly
steroidal saponins. OP crude extracts and APIs exhibited cytotoxicity against a panel of
melanoma cell lines, PLX4032-resistant A375-R melanoma cells, and HRAS Q61L PDV
keratinocytes, but showed minimal toxicity on normal keratinocytes and fibroblasts. In a
xenograft mouse model, OP_APIs dose-dependently suppressed A375-R tumor growth,
achieving inhibition of 84% and 80% relative to tumor control (100%) in female and male mice,
respectively. Immunohistochemistry revealed reduced expression of Ki-67, lipid metabolic
hydrolase I/II, pMEK1/2 and pERK1/2, and androgen receptor. Primary metabolomics
indicated significant alterations in amino acid and fatty acid metabolism between untreated
tumors and APIs-treated groups. OP_APIs more significantly decreased AR, pERK1/2, and
VEGFA protein levels in drug resistant A375-R cells than those in drug sensitive A375 cells.
Our findings highlight OP_APIs as a promising candidate for overcoming vemurafenib
resistance in melanoma.

Keywords: Drug-resistant melanoma; BRAF V600E inhibitor; Vemurafenib; Medicinal orchid