Piperlongumine induces ROS mediated apoptosis by transcriptional regulation of SMAD4/P21/P53 genes and synergizes with doxorubicin in osteosarcoma cells

• Published in: Chemico-biological interactions 2022-02, Vol.354, p.109832, Article 109832
• Main Authors: Rawat, Laxminarayan, Nayak, Vijayashree
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Bone Neoplasms - drug therapy; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Dioxolanes - pharmacology; Doxorubicin; Doxorubicin - pharmacology; Drug Synergism; Gene Expression Regulation, Neoplastic - drug effects; Herbal medicine; Humans; Natural product; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - metabolism; Osteosarcoma - pathology; Piperidones; Piperlongumine; Reactive Oxygen Species - metabolism; SMAD4; Smad4 Protein - genetics; Smad4 Protein - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0009-2797; 1872-7786; 1872-7786
• DOI: 10.1016/j.cbi.2022.109832

Piperlongumine is a herbal drug, with well-known anti-microbial and anti-neoplastic properties. The anti-carcinogenic potential of piperlongumine has been extensively explored for breast, colorectal, lungs, pancreatic, prostate, and oral carcinoma. However, a few numbers of studies are available on its bio-activity in osteosarcoma. Therefore, the present study aimed at exploring the therapeutic potential and possible mechanisms of action of piperlongumine in three human osteosarcoma cell lines in-vitro. The cytotoxicity of piperlongumine was determined by MTT assay, which shows dose and time-dependent inhibition of MG-63, 143B and KHOS/NP cells. Piperlongumine arrest the cells in G2/M phase of cell cycle and increases reactive oxygen species production, which possibly leads to lethal oxidative stress and apoptosis. Piperlongumine treatment significantly upregulated the expression of genes BAX, P21, P53, and SMAD4; while the BCL-2, SURVIVIN, TNFA, and NFKB genes expression was found down-regulated. Furthermore, piperlongumine exposure inhibited the migration of osteosarcoma cells as the expression of migration marker genes CDH2, CTNNB1, FN1, and TWIST were found to be down-regulated. The drug combination studies show the synergistic effect of piperlongumine with the conventional chemotherapeutic drug doxorubicin in osteosarcoma cells. Taken together, the above results suggest that PL displays anticancer properties against osteosarcoma and can be used as a therapeutic agent for osteosarcoma treatment in clinical settings. [Display omitted] •PL induces apoptosis in osteosarcoma cells by disturbing ROS homeostasis.•PL treatment regulates the NFKB and SMAD4 expression to induce apoptosis.•PL synergizes with doxorubicin and enhances the therapeutic efficacy.