Abstract
Purpose: Pentagamavunon-1 (PGV-1) is a curcumin analogue that shows cytotoxic activity in various cancer cells. In this study, we evaluated the effect of PGV-1 on a highly metastatic breast cancer cell line, the 4T1 cells, as an anti-metastatic and anti-proliferative agent. Methods: Cell viability was evaluated using MTT assay; while cell cycle profile, apoptosis incidence, and ROS intracellular level were determined by flow cytometry. Cell senescence was observed under senescence-associated-β-galactosidase (SA-β-gal) staining assay. The expression of matrixmetalloproteinase-9 (MMP-9) was determined using immunoreaction based-ELISA, while other proteins expression were detected using immunoblotting. Results: Curcumin and PGV-1 showed cytotoxic effects on 4T1 cells with IC50 value of 50 and 4 µM, respectively. The cytotoxic activity of PGV-1 was correlated to the induction of G2/M cell cycle arrest and cell senescence. Furthermore, PGV-1 increased the accumulation of intracellular ROS level. We also revealed that PGV-1 bound to several ROS-metabolizing enzymes, including glyoxalase I (GLO1), peroxiredoxin 1 (PRDX1), N-ribosyldihydronicotinamide: quinone reductase 2 (NQO2), aldo-keto reductase family 1 member c1 (AKR1C1). As an antimetastatic agent, PGV-1 showed less inhibitory effect on cell migration compared to curcumin. However, PGV-1 significantly decreased MMP-9 protein expression in a dose-dependent manner suggesting it still potent to inhibit metastatic cells. Conclusion: Overall, our findings suggest that PGV-1 is potential to be developed as an antiproliferative and anti-metastatic agent.
Highlights
As a complex disease with the complexity of molecular based-physiological alterations, cancer challenges scientist to develop a new anti-cancer drug with specific mechanism.[1]
We revealed that PGV-1 bound to several reactive oxygen species (ROS)-metabolizing enzymes, including glyoxalase I (GLO1), peroxiredoxin 1 (PRDX1), N-ribosyldihydronicotinamide: quinone reductase 2 (NQO2), aldo-keto reductase family 1 member c1 (AKR1C1)
Anti-cancer properties of curcumin and its analogues have been reviewed in several papers.[15,16,17,18]
Summary
As a complex disease with the complexity of molecular based-physiological alterations, cancer challenges scientist to develop a new anti-cancer drug with specific mechanism.[1]. We use 4T1 cells that are characterized by the highly proliferative and metastatic activities.[6,7] This highly metastatic cancer cell line is a suitable model to explore the new anti-cancer agent targeting on cell proliferation and metastasis. There are numerous molecular pathways underlying the proliferative and metastatic phenomenon involving tightly regulation of energy metabolism.[8] In this regard, intracellular reactive oxygen species (ROS) level is getting a highlight as a target of anticancer strategy.[9] Interestingly, we found a new anticancer mechanism of curcumin through the ROS metabolic pathway. Curcumin exhibits cytotoxic activity in K562 cells, a leukemic cell line, by inhibiting multiple antioxidant enzymes, subsequently increasing intracellular ROS level and inducing cancer cell death.[10]
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