Involvement of the NF‐κB and PI3K/Akt/mTOR pathways in cell death triggered by stypoldione, an o‐quinone isolated from the brown algae Stypopodium zonale

• Published in: Environmental toxicology Vol. 37; no. 6; pp. 1297 - 1309
• Main Authors: Walter, Laura O., Maioral, Mariana F., Silva, Lisandra O., Speer, Douglas B., Campbell, Sanjay C., Gallimore, Winklet, Falkenberg, Miriam B., Santos‐Silva, Maria Cláudia
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.06.2022; Wiley Subscription Services, Inc
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Algae; Annexin V; Apoptosis; Apoptosis-inducing factor; Caspase; Cell death; Cell morphology; Cell viability; Cytology; Cytotoxicity; Drug development; Haemolysis; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Malignancy; Multiple myeloma; NF-kappa B - metabolism; NF‐κB; Peripheral blood mononuclear cells; Phaeophyceae; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; quinone; Quinones; Quinones - pharmacology; Reactive oxygen species; Reactive Oxygen Species - metabolism; ROS; Stypopodium zonale; Survival; Survivin; TOR protein; TOR Serine-Threonine Kinases - metabolism; Toxicity; NF-κB; apoptosis; multiple myeloma; ROS; quinone
• ISSN: 1520-4081; 1522-7278
• DOI: 10.1002/tox.23484

Multiple myeloma (MM) is a clonal plasma cell malignancy that remains incurable to date. Thus, the aims of this study were to evaluate the involvement of the NF‐κB and PI3K/Akt/mTOR pathways in the cytotoxicity of stypoldione, an o‐quinone isolated from the brown algae Stypopodium zonale, in MM cells (MM1.S). The cytotoxic effect was evaluated in MM1.S cells and peripheral blood mononuclear cells (PBMCs) by MTT assay. The stypoldione reduced the cell viability of MM1.S cells in a concentration and time‐dependent manner (IC50 in MM.1S from 2.55 to 5.38 μM). However, it was also cytotoxic to PBMCs, but at a lower range. Additionally, no significant hemolysis was observed even at concentration up to 10 times the IC50. Apoptotic cell death was confirmed by cell morphology and Annexin V‐FITC assay. Stypoldione induced intrinsic and extrinsic apoptosis by increasing FasR expression and reactive oxygen species (ROS) production, inverting the Bax/Bcl‐2 ratio, and inducing ΔΨm loss, which resulted in AIF release and caspase‐3 activation. It also increased Ki‐67 and survivin expression and inhibited the NF‐κB and PI3K/Akt/mTOR pathways. These results suggest that stypoldione is a good candidate for the development of new drugs for MM treatment.