School of Biological Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia.
Centre for Drug Research, Universiti Sains Malaysia, 11800 Penang, Malaysia.
J Ethnopharmacol. 2021 Oct 28;279:114391. doi: 10.1016/j.jep.2021.114391. Epub 2021 Jul 2.
Mitragyna speciosa (Korth.) or kratom is a medicinal plant indigenous to Southeast Asia. The leaf of M. speciosa is used as a remedy in pain management including cancer related pain, in a similar way as opioids and cannabis. Despite its well-known analgesic effect, there is a scarce of information on the cancer-suppressing potential of M. speciosa and its active constituents.
To assess the potential applicability of M. speciosa alkaloids (mitragynine, speciociliatine or paynantheine) as chemosensitizers for cisplatin in Nasopharyngeal carcinoma (NPC) cell lines.
The cytotoxic effects of the extracts, fractions and compounds were determined by conducting in vitro cytotoxicity assays. Based on the cytotoxic screening, the alkaloid extract of M. speciosa exhibited potent inhibitory effect on the NPC cell line NPC/HK1, and therefore, was chosen for further fractionation and purification. NPC cell lines NPC/HK1 and C666-1 were treated with combinations of cisplatin and M. speciosa alkaloids combinations in 2D monolayer culture. The effect of cisplatin and mitragynine as a combination on cell migration was tested using in vitro wound healing and spheroid invasion assays.
In our bioassay guided isolation, both methanolic and alkaloid extracts showed mild to moderate cytotoxic effect against the NPC/HK1 cell line. Both NPC cell lines (NPC/HK1 and C666-1) were insensitive to single agent and combination treatments of the M. speciosa alkaloids. However, mitragynine and speciociliatine sensitized the NPC/HK1 and C666-1 cells to cisplatin at ~4- and >5-fold, respectively in 2D monolayer culture. The combination of mitragynine and cisplatin also significantly inhibited cell migration of the NPC cell lines. Similarly, the combination also of mitragynine and cisplatin inhibited growth and invasion of NPC/HK1 spheroids in a dose-dependent manner. In addition, the spheroids did not rapidly develop resistance to the drug combinations at higher concentrations over 10 days.
Our data indicate that both mitragynine and speciociliatine could be potential chemosensitizers for cisplatin. Further elucidation focusing on the drug mechanistic studies and in vivo studies are necessary to support delineate the therapeutic applicability of M. speciosa alkaloids for NPC treatment.
Mitragyna speciosa（Korth.）或 kratom 是一种原产于东南亚的药用植物。该植物的叶子被用作治疗疼痛的药物，包括与癌症相关的疼痛，其作用方式与阿片类药物和大麻类似。尽管它具有众所周知的镇痛作用，但关于 M. speciosa 的抗癌潜力及其活性成分的信息却很少。
评估 M. speciosa 生物碱（mitragynine、specio cil iatine 或 paynantheine）作为顺铂在鼻咽癌（NPC）细胞系中的化学增敏剂的潜在适用性。
通过体外细胞毒性测定来确定提取物、馏分和化合物的细胞毒性作用。基于细胞毒性筛选，M. speciosa 的生物碱提取物对 NPC 细胞系 NPC/HK1 表现出强烈的抑制作用，因此选择进一步进行分离和纯化。在 2D 单层培养中，用顺铂和 M. speciosa 生物碱组合处理 NPC 细胞系 NPC/HK1 和 C666-1。使用体外划痕愈合和球体侵袭测定法测试顺铂和 mitragynine 作为组合对细胞迁移的影响。
在我们的生物测定指导分离中，甲醇提取物和生物碱提取物对 NPC/HK1 细胞系均表现出温和至中度的细胞毒性作用。两种 NPC 细胞系（NPC/HK1 和 C666-1）对 M. speciosa 生物碱的单一药物和组合治疗均不敏感。然而，在 2D 单层培养中，mitragynine 和 speciociliatine 分别将 NPC/HK1 和 C666-1 细胞对顺铂的敏感性提高了约 4 倍和 5 倍。mitragynine 和 cisplatin 的组合也显著抑制了 NPC 细胞系的细胞迁移。同样，该组合还以剂量依赖的方式抑制 NPC/HK1 球体的生长和侵袭。此外，在 10 天内，球体在较高浓度下不会迅速对药物组合产生耐药性。
我们的数据表明，mitragynine 和 speciociliatine 均可作为顺铂的潜在化学增敏剂。需要进一步阐明侧重于药物机制研究和体内研究的结果，以支持阐述 M. speciosa 生物碱在 NPC 治疗中的治疗应用。
