Therapeutic Effect and Molecular Mechanism of the Ultra-Low Molecule Compound K on Multiple Myeloma

Introduction: Multiple myeloma (MM) is an incurable hematologic cancer that originates from plasma cells and occurs primarily in patients over 60. The prognosis of MM has improved after the introduction of new treatments, such as thalidomide, bortezomib, and lenalidomide. However, in recurrent and refractory MM patients, factors such as age and drug toxicity are important when choosing treatment options. Therefore, new drugs with little toxicity are needed. Through previous research, we confirmed that the triterpene compound series has a killing effect on multiple myeloma cells, and conducted a nonclinical trial.

Methods: The killing effect of the hit compounds on MM cell lines (ARH77, U266, and RPMI8226) was examined using a sulforhodamine B assay. Apoptosis mechanisms were investigated in vitro by western blot and apoptotic protein array. Complex immunocompromised mice were established by injecting RPMI8226-GFP-FLuc cells through the tail vein. Efficacy of the KBB-N1 activity was assessed following daily oral administration (20 mg/kg/day) for 3 weeks and tail vein (7 mg/kg/day) infusions for 3 days a week at daily intervals. Toxicity, pharmacokinetics, and molecular docking analyses were performed according to the established protocols.

Results: KBB-N1 was identified as an MM-targeted hit compound with cytotoxic effects. Severe suppression of normal hematopoietic stem cell function was observed with lenalidomide administration at a concentration of 25 μM. However, this toxicity was not observed when KBB-N1 was administered at doses up to 60 μM. KBB-N1 activity involves PARP cleavage and caspase activation in the apoptotic pathway. Furthermore, KBB-N1 inhibited cell growth and exerted cytotoxicity. KBB-N1 induced apoptosis by activating the P53 apoptosis pathway in MM cells. In vivo, all untreated tumor-bearing mice showed rapid tumor growth and severe plasmacytomas, which led to death within 7 weeks. Mice treated with KBB-N1 had significantly inhibited tumor growth and longer survival times. The molecular docking assay revealed the optimal docking conformation binding energy of KBB-N1 with docking scores (kcal/M) of -7.6 for phosphorylated p53.

Conclusions: This study demonstrated that KBB-N1, an ultra-low molecular weight ginsenoside compound K, effectively treated MM by increasing the expression of phosphorylated p53. Given its minimal toxicity to hematopoietic stem cells and major organs, KBB-N1 is a promising new drug for treating MM in older patients.

No relevant conflicts of interest to declare.