Antiproliferative and Antiangiogenic Effects of Punica granatum Juice (PGJ) in Multiple Myeloma (MM)

Abstract

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC) in the bone marrow (BM) leading to bone destruction and BM failure. Despite recent advances in pharmacological therapy, MM remains a largely incurable pathology. Therefore, novel effective and less toxic agents are urgently necessary. In the last few years, pomegranate has been studied for its potential therapeutic properties including treatment and prevention of cancer. Pomegranate juice (PGJ) contains a number of potential active compounds including organic acids, vitamins, sugars, and phenolic components that are all responsible of the pro-apoptotic effects observed in tumor cell line. The aim of present investigation is to assess the antiproliferative and antiangiogenic potential of the PGJ in human multiple myeloma cell lines. Our data demonstrate the anti-proliferative potential of PGJ in MM cells; its ability to induce G0/G1 cell cycle block and its anti-angiogenic effects. Interestingly, sequential combination of bortezomib/PGJ improved the cytotoxic effect of the proteosome inhibitor. We investigated the effect of PGJ on angiogenesis and cell migration/invasion. Interestingly, we observed an inhibitory effect on the tube formation, microvessel outgrowth aorting ring and decreased cell migration and invasion as showed by wound-healing and transwell assays, respectively. Analysis of angiogenic genes expression in endothelial cells confirmed the anti-angiogenic properties of pomegranate. Therefore, PGJ administration could represent a good tool in order to identify novel therapeutic strategies for MM treatment, exploiting its anti-proliferative and anti-angiogenic effects. Finally, the present research supports the evidence that PGJ could play a key role of a future therapeutic approach for treatment of MM in order to optimize the pharmacological effect of bortezomib, especially as adjuvant after treatment.

Antimicrobial and Anti-Proliferative Effects of Skin Mucus Derived from Dasyatis pastinaca (Linnaeus, 1758)

“…Human lymphocytes and monocytes were isolated, after informed consent, from fresh buffy coat of healthy volunteers provided by the Transfusional Center of E. Muscatello Hospital—Augusta (SR). Monocytes and lymphocytes then were purified from the lymphomonocytic population by positive isolation using magnetic beads coated with goat anti-mouse CD14 + IgG and anti-mouse CD3 + IgG respectively (MiltenyiBiotec GmbH, Bergisch Gladbach, Germany) [ 23 ].…”

Anti‐angiogenic effect of quercetin and its 8‐methyl pentamethyl ether derivative in human microvascular endothelial cells

“…Cells were plated in 96 well plates at a density of 1 × 10 4 cells/well and were grown in complete medium in the absence or presence of increasing Q and Q derivatives concentrations (ie 25, 50 and 100 μM) for 24 and 48 hours. After the treatments, the cells were incubated with MTT for 4 hours and then 100 μL dimethyl sulfoxide was added and the absorbance was read at 590 nm, as previously described . To test cell proliferation, the cells were incubated with 25 ng/mL VEGF‐A or CM, as positive controls, and with CM containing 25 μmol/L Q or its derivatives.…”

“…After the treatments, the cells were incubated with MTT for 4 hours and then 100 μL dimethyl sulfoxide was added and the absorbance was read at 590 nm, as previously described. 35 To test cell proliferation, the cells were incubated with 25 ng/mL VEGF-A or CM, as positive controls, and with CM containing 25 μmol/L Q or its derivatives. Bromodeoxyuridine (BrdU [Abcam, Cambridge, UK]) was added 4 hours before the end of the 24-hour incubation period.…”

Possible use of Punica granatum (Pomegranate) in cancer therapy

“…It has been shown that the polyphenolic-rich extracts of the non-edible parts of Punica granatum, such as leaves, stem, and flower extract, elicit anti-proliferative and apoptotic effects, with a rise in loss of mitochondrial membrane potential and cell cycle arrest, and reduced expression of MMP in U266 multiple myeloma cells [127]. Moreover, PJ showed anti-proliferative and anti-angiogenic properties and induced cell cycle arrest at the G0/G1 phase in multiple myeloma cells [128]. Ellagic acid obtained from the pomegranate peel extract was found to inhibit Hela cell invasion via suppression of the AKT/mTOR signaling pathway due to augmentation in the level of IGFBP7 expression [129].…”