Neosetophomone B induces apoptosis in multiple myeloma cells via targeting of AKT/SKP2 signaling pathway

• Published in: Cell biology international Vol. 48; no. 2; pp. 190 - 200
• Main Authors: Kuttikrishnan, Shilpa, Ahmad, Fareed, Mateo, Jericha M., Prabhu, Kirti S., El‐Elimat, Tamam, Oberlies, Nicholas H., Pearce, Cedric J., Akil, Ammira S. Alshabeeb, Bhat, Ajaz A., Alali, Feras Q., Uddin, Shahab
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-02-2024; John Wiley and Sons Inc
• Subjects: AKT; AKT protein; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; Apoptosis; BAX protein; Bcl-2 protein; Bortezomib; Bortezomib - pharmacology; Cancer therapies; Caspase; caspases; Cell growth; Cell Line, Tumor; Cell Proliferation; Cytotoxicity; Drug resistance; drug synergy; GTP-binding protein; Humans; Kinases; Malignancy; Molecular modelling; Multiple myeloma; Multiple Myeloma - metabolism; Natural products; neosetophomone B; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; SKP2; drug synergy; multiple myeloma; AKT; SKP2; caspases; neosetophomone B
• ISSN: 1065-6995; 1095-8355
• DOI: 10.1002/cbin.12101

Multiple myeloma (MM) is a hematologic malignancy associated with malignant plasma cell proliferation in the bone marrow. Despite the available treatments, drug resistance and adverse side effects pose significant challenges, underscoring the need for alternative therapeutic strategies. Natural products, like the fungal metabolite neosetophomone B (NSP‐B), have emerged as potential therapeutic agents due to their bioactive properties. Our study investigated NSP‐B's antitumor effects on MM cell lines (U266 and RPMI8226) and the involved molecular mechanisms. NSP‐B demonstrated significant growth inhibition and apoptotic induction, triggered by reduced AKT activation and downregulation of the inhibitors of apoptotic proteins and S‐phase kinase protein. This was accompanied by an upregulation of p21Kip1 and p27Cip1 and an elevated Bax/BCL2 ratio, culminating in caspase‐dependent apoptosis. Interestingly, NSP‐B also enhanced the cytotoxicity of bortezomib (BTZ), an existing MM treatment. Overall, our findings demonstrated that NSP‐B induces caspase‐dependent apoptosis, increases cell damage, and suppresses MM cell proliferation while improving the cytotoxic impact of BTZ. These findings suggest that NSP‐B can be used alone or in combination with other medicines to treat MM, highlighting its importance as a promising phytoconstituent in cancer therapy.