Piperlongumine, a piper alkaloid, enhances the efficacy of doxorubicin in breast cancer: involvement of glucose import, ROS, NF-κB and lncRNAs.
Nikee AwastheeAnusmita ShekherVipin RaiSumit S VermaShruti MishraAnupam DhasmanaSubash Chandra GuptaPublished in: Apoptosis : an international journal on programmed cell death (2022)
Piperlongumine (PL, piplartine) is an alkaloid derived from the Piper longum L. (long pepper) roots. Originally discovered in 1961, the biological activities of this molecule against some cancer types was reported during the last decade. Whether PL can synergize with doxorubicin and the underlying mechanism in breast cancer remains elusive. Herein, we report the activities of PL in numerous breast cancer cell lines. PL reduced the migration and colony formation by cancer cells. An enhancement in the sub-G1 population, reduction in the mitochondrial membrane potential, chromatin condensation, DNA laddering and suppression in the cell survival proteins was observed by the alkaloid. Further, PL induced ROS generation in breast cancer cells. While TNF-α induced p65 nuclear translocation, PL suppressed the translocation in cancer cells. The expression of lncRNAs such as MEG3, GAS5 and H19 were also modulated by the alkaloid. The molecular docking studies revealed that PL can interact with both p65 and p50 subunits. PL reduced the glucose import and altered the pH of the medium towards the alkaline side. PL also suppressed the expression of glucose and lactate transporter in breast cancer cells. In tumor bearing mouse model, PL was found to synergize with doxorubicin and reduced the size, volume and weight of the tumor. Overall, the effects of doxorubicin in cancer cells are enhanced by PL. The modulation of glucose import, NF-κB activation and lncRNAs expression may have contributory role for the activities of PL in breast cancer.
Keyphrases
- molecular docking
- poor prognosis
- breast cancer cells
- drug delivery
- dna damage
- signaling pathway
- blood glucose
- oxidative stress
- gene expression
- rheumatoid arthritis
- type diabetes
- squamous cell carcinoma
- metabolic syndrome
- adipose tissue
- cell proliferation
- cell death
- binding protein
- transcription factor
- weight loss
- lps induced
- genome wide
- insulin resistance
- single molecule
- skeletal muscle
- risk assessment
- carbon dioxide
- stress induced
- case control