Mitragyna alkaloids derived from the medicinal plant Mitragyna speciosa Korth. and cisplatin synergistically inhibit cell proliferation of Nasopharyngeal Carcinoma (NPC) cell lines

Ethnopharmacological relevanceMitragyna speciosa (Korth.) or kratom is a medicinal plant indigenous to Southeast Asia. The leaves of M. speciosa is used as a medication 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. Aim of the studyTo assess the potential applicability of M. speciosa alkaloids (mitragynine, speciociliatine or paynantheine) as chemosensitizers for cisplatin in Nasopharyngeal carcinoma (NPC) cell lines. Materials and MethodsThe 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 HK-1, and therefore, was chosen for further fractionation and purification. NPC cell lines HK-1 and C666-1 were treated with combinations of cisplatin and M. speciosa alkaloids in 2D monolayer culture. The effect of the drug combination on cell migration was tested using in vitro wound healing and spheroid invasion assays. ResultsIn our bioassay guided isolation, both methanolic and alkaloid extracts showed mild to moderate cytotoxic effect against the HK-1 cell line. Both NPC cell lines were insensitive to single agent and combination treatments of the M. speciosa alkaloids. However, mitragynine and speciociliatine sensitised the HK-1 and C666-1 to cisplatin ~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, combination of mitragynine and cisplatin inhibited growth and invasion of HK-1 spheroids in a dose-dependent manner. Moreover, the spheroids did not rapidly develop resistance to the drug combinations at high concentrations over 10 days. ConclusionCollectively, data shows that both mitragynine and speciociliatine could be potential chemosensitizers for cisplatin. Further extensive drug mechanistic studies and investigations in animal models are necessary to delineate the applicability of M. speciosa alkaloids for NPC therapy.