Spice-derived phenolic, malabaricone B induces mitochondrial damage in lung cancer cells via a p53-independent pathway.

Abstract

The spice-derived phenolic, malabaricone B (mal B) showed selective toxicity to human lung cancer (A549), malignant melanoma (A375) and T cell leukemia (Jurkat) cell lines, without showing toxicity to human normal intestinal (INT407), human kidney (HEK293) and lung fibroblast (WI-38) cells. Among the chosen cancer cell lines, mal B showed maximum cytotoxicity to the A549 cells (IC50 = 8.1 ± 1.0 μM), which was significantly better than that of curcumin (IC50 = 26.7 ± 3.1 μM). Further morphological studies by phase contrast microscopy and a clonogenic assay of the A549 cells revealed that mal B treatment increased the number of shrinking cells and also abolished the clonal proliferation of the cells. Mal B induced apoptotic cell death was confirmed by DNA laddering and quantified by cytoplasmic oligonucleosome formation and annexin V/PI assays. The mal B-induced apoptosis was mediated by an increase in the intracellular reactive oxygen species (ROS), because the cell-permeable antioxidants, N-acetylcysteine (NAC) and PEG-SOD, strongly inhibited its cytotoxicity to the A549 cells. Mal B increased the BAX level while simultaneously decreasing the BCL-2 and BCL-XL levels in the A549 cells, triggering the mitochondrial apoptotic pathway as revealed from the release of cytochrome c, and the activation of caspase-9 and caspase-3. Pre-treatment of cells with caspase-9, caspase-3 and pan-caspase inhibitors made them more resistant to mal B treatment. This effect of mal B was strongly associated with the concomitant decrease in anti-apoptotic (IAP1, IAP2 and survivin), angiogenic (growth factors) and cancer invasiveness (matrix metalloproteinase-9, COX-2) modulating proteins. Mal B induced cytotoxicity was unaffected by the shRNA-mediated depletion of p53 in A549 cells. Most importantly, mal B sensitized a wide range of human carcinoma cells regardless of their p53 status. Finally, mal B (100 mg kg-1) also inhibited lung tumor (xenograft) growth in SCID mice.

• Authors: Mrityunjay Tyagi , Biswanath Maity , Bhaskar Saha , Ajay Kumar Bauri , Mahesh Subramanian , Subrata Chattopadhyay , Birija Sankar Patro
• Journal: Food & function (Food Funct) Vol. 9 Issue 11 Pg. 5715-5727 (Nov 14 2018) ISSN: 2042-650X [Electronic] England
• PMID: 30318526 (Publication Type: Journal Article)

Chemical References

• BAX protein, human
• Reactive Oxygen Species
• Resorcinols
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• malabaricone B
• Cytochromes c
• CASP3 protein, human
• CASP9 protein, human
• Caspase 3
• Caspase 9
• Curcumin

Topics

• A549 Cells
• Animals
• Apoptosis (drug effects)
• Caspase 3 (genetics, metabolism)
• Caspase 9 (genetics, metabolism)
• Cell Line, Tumor
• Curcumin (pharmacology)
• Cytochromes c (metabolism)
• DNA Fragmentation
• HEK293 Cells
• Humans
• Inhibitory Concentration 50
• Lung Neoplasms (drug therapy)
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, SCID
• Mitochondria (drug effects)
• Reactive Oxygen Species (metabolism)
• Resorcinols (pharmacology)
• Tumor Suppressor Protein p53 (genetics)
• Xenograft Model Antitumor Assays
• bcl-2-Associated X Protein (genetics, metabolism)