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

ABSTRACT: 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.

SUBMITTER: Kuttikrishnan S

PROVIDER: S-EPMC10952688 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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

Kuttikrishnan Shilpa S Ahmad Fareed F Mateo Jericha M JM Prabhu Kirti S KS El-Elimat Tamam T Oberlies Nicholas H NH Pearce Cedric J CJ Akil Ammira S Alshabeeb ASA Bhat Ajaz A AA Alali Feras Q FQ Uddin Shahab S

Cell biology international 20231026 2

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 l ...[more]

PMID: 37885161

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Project description:Sanguinarine (SNG), a benzophenanthridine alkaloid, has displayed various anticancer abilities in several vivo and in vitro studies. However, the anticancer potential of SNG is yet to be established in multiple myeloma (MM), a mostly incurable malignancy of plasma cells. In this study, we aimed to investigate the potential anti-proliferative and pro-apoptotic activities of SNG in a panel of MM cell lines (U266, IM9, MM1S, and RPMI-8226). SNG treatment of MM cells resulted in a dose-dependent decrease in cell viability through mitochondrial membrane potential loss and activation of caspase 3, 9, and cleavage of PARP. Pre-treatment of MM cells with a universal caspase inhibitor, Z-VAD-FMK, prevented SNG mediated loss of cell viability, apoptosis, and caspase activation, confirming that SNG-mediated apoptosis is caspase-dependent. The SNG-mediated apoptosis appears to be resulted from suppression of the constitutively active STAT3 with a concomitant increase in expression of protein tyrosine phosphatase (SHP-1). SNG treatment of MM cells leads to down-regulation of the anti-apoptotic proteins including cyclin D, Bcl-2, Bclxl, and XIAP. In addition, it also upregulates pro-apoptotic protein, Bax. SNG mediated cellular DNA damage in MM cell lines by induction of oxidative stress through the generation of reactive oxygen species and depletion of glutathione. Finally, the subtoxic concentration of SNG enhanced the cytotoxic effects of anticancer drugs bortezomib (BTZ) by suppressing the viability of MM cells via induction of caspase-mediated apoptosis. Altogether our findings demonstrate that SNG induces mitochondrial and caspase-dependent apoptosis, generates oxidative stress, and suppresses MM cell lines proliferation. In addition, co-treatment of MM cell lines with sub-toxic doses of SNG and BTZ potentiated the cytotoxic activity. These results would suggest that SNG could be developed into therapeutic agent either alone or in combination with other anticancer drugs in MM.

Project description:Multiple myeloma (MM) is a hematological malignancy characterized by the unrestricted proliferation of plasma cells that secrete immunoglobulin in the bone marrow. Extracted primarily from Anemone raddeana regel, Raddeanin A (RA) is a natural triterpenoid saponin compound with anti-inflammatory and anti-tumor activities. However, most research on the anti-tumor effects of RA has concentrated on solid tumors, with little exploration into non-solid tumors like MM. Furthermore, there is a dearth of research investigating the interplay between RA and MM, encompassing their interaction targets and mechanisms. This study aims to delve into the biological activity and molecular mechanism of RA's anti-MM properties through the lens of network pharmacology and experimental validation. The findings from GO enrichment analysis, KEGG enrichment analysis, and molecular docking prediction suggested a potential correlation between the MAPK signaling pathway, including the MAPK1 gene (also known as ERK2), and the impact of RA on MM. Results from the CCK-8 assay revealed a time-dependent and concentration-dependent inhibition of proliferation in MM cell lines treated with RA. Notably, in the cell lines used for the test, the IC50 values for MM.1 S cells were 1.616 µM at 24 H and 1.058 µM at 48 H, for MM.1R cells were 3.905 µM at 24 H and 2.18 µM at 48 H, while for RPMI 8226 cells, they were 6.091 µM at 24 H and 3.438 µM at 48 H. The PI, Annexin V-FITC/PI, and JC-1 staining showed that RA could arrest the cell cycle in the G2 phase, cause apoptosis, and induce the change of mitochondrial membrane potential (MMP) in MM cells. Treated with RA, the Western blot analysis showed that the expression levels of Bim, Cleaved Caspase 3/9, and Cleaved PARP were increased, and the expression level of Mcl-1 was decreased in MM cells. Concurrently, the phosphorylated protein expression levels of p-ERK1/2, p-MSK1, p-P90RSK, and p-MEK1/2 were diminished following RA treatment. These results suggest that RA has the activity of anti-MM, and the MAPK/ERK signaling pathway is involved in the growth inhibition effect of RA on MM cells via cycle arrest and mitochondrial-pathway-dependent apoptosis.

Dataset Information

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

Publications

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

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