Mitragyna speciosa Alkaloids Inhibit Proliferation and Metastasis in Luminal A and Triple-Negative Breast Cancer Mediated by AKT1 and Mortalin

Breast cancer, including subtypes luminal A and triple-negative breast cancer (TNBC), presents considerable clinical challenges due to its heterogeneity and resistance to current treatments. This highlights an urgent need for new therapeutic strategies targeting multiple oncogenic pathways. This study assessed the anti-cancer efficacy of kratom ( Mitragyna speciosa ) alkaloids on Luminal A (MCF-7) and TNBC (MDA-MB-231) cell lines. We evaluate the potential anticancer capacities of kratom alkaloids using a combination of network pharmacology, molecular docking, and dynamics, alongside in vitro and molecular experiments. This multilevel approach focused on assessing the effects on proliferation, migration, invasion, and cell cycle, as well as on identifying the underlying molecular targets. Kratom alkaloids markedly decreased cellular proliferation, induced G2/M phase arrest, and suppressed tumoral metastasis-associated capacities. These effects were mediated by the downregulation of AKT1 and mortalin (HSPA9), leading to the reactivation of p53 signalling. Molecular docking validated robust binding affinities of alkaloids to both targets. The Cancer Genome Atlas (TCGA) analysis corroborated the alkaloids clinical significance in breast cancer. The results highlight a significant therapeutic potential for Kratom alkaloids as dual-target medicines demonstrating both anti-proliferative and anti-metastatic effects in Luminal A and TNBC models.