Antitumor activity and mechanism of action of alkaloids from Alocasia macrorrhiza (giant taro) against nasopharyngeal carcinoma in vitro and in vivo: First identification of AMD-8's ATM inhibitory role in nasopharyngeal carcinoma.

Alocasia macrorrhiza (Giant taro), widely cultivated in tropical areas, especially southern China, has long been used in folk medicine for treating cancers, including nasopharyngeal carcinoma (NPC). This study evaluated the anti-nasopharyngeal carcinoma effects of the total alkaloids of A. macrorrhiza (AMA) and AMD-8, a bioactive alkaloid isolated from AMA, and investigated the underlying mechanisms. In vitro, MTT and colony formation assays assessed antiproliferative activity, while apoptosis and DNA damage were analyzed by Hoechst staining, Annexin V/PI flow cytometry, immunofluorescence, and Western blot. In vivo, the efficacy and safety were examined using a CNE1 xenograft model in BALB/c-nude mice. Transcriptomic analysis of tumor tissue was performed to explore pharmacological mechanisms. AMA and AMD-8 showed strong cytotoxicity against CNE1 (IC50 = 30.80 μg/mL and 22.53 μM) and CNE2 cells (IC50 = 30.54 μg/mL and 27.93 μM). Both induced apoptosis (up to 40 %) and DNA damage, with cell cycle arrest at G2/M phase (CNE1) and G0/G1 phase (CNE2). AMA also disrupted the homologous recombination repair (HRR) pathway. In vivo, AMA significantly inhibited tumor growth with well-tolerability. Transcriptomics analysis showed changes in cell cycle and HRR. Western blot confirmed AMA promoted apoptosis and suppressed HRR in tumors. The up-regulated expression of cleaved-caspase-3 and PARP1 suggested that AMA promoted apoptosis, the decreased BRCA2, ATM, CtIP, NBS1, Rad54 and Rad51 confirmed AMA suppressed HRR. AMA demonstrates significant antitumor activity against NPC by inducing apoptosis, causing cell cycle arrest, and inhibiting HRR. These findings suggest AMA as a promising therapeutic or adjuvant agent for NPC.