Bioinformatics Analysis Confirms the Target Protein Underlying Mitotic Catastrophe of 4T1 Cells under Combinatorial Treatment of PGV-1 and Galangin

Abstract

Pentagamavunon-1 (PGV-1), a potential chemopreventive agent with a strong cytotoxic effect, modulates prometaphase arrest. Improvement to get higher effectiveness of PGV-1 is a new challenge. A previous study reported that the natural compound, galangin, has antiproliferative activity against cancer cells with a lower cytotoxicity effect. This study aims to develop a combinatorial treatment of PGV-1 and galangin as an anticancer agent with higher effectiveness than a single agent. In this study, 4T1, a TNBC model cell, was treated with a combination of PGV-1 and galangin. As a result, PGV-1 and galangin showed a cytotoxic effect with IC50 values of 8 and 120 µM, respectively. Combining those chemicals has a synergistic impact, as shown by the combination index (CI) value of 1. Staining with the May Grunwald-Giemsa reagent indicated mitotic catastrophe evidence, characterized by micronuclear and multinucleated morphology. Moreover, the senescence percentage was higher than the single treatment. Furthermore, bioinformatics investigations showed that PGV-1 and galangin target CDK1, PLK1, and AURKB, overexpression proteins in TNBC that are essential in regulating cell cycle arrest. In conclusion, the combination of PGV-1 and galangin exhibit a synergistic effect and potential to be a chemotherapeutic drug by the mechanism of mitotic catastrophe and senescence induction.

The Synergistic Effect of Combination of Pentagamavunone-1 with Diosmin, Galangin, and Piperine in WiDr Colon Cancer Cells: <i>In vitro</i> and Target Protein Prediction

“…In this study we employed a direct counting method rather than an enzymatic colorimetric assay (Aslanturk 2017;Lestari et al 2019). Nevertheless, the tested natural compounds displayed a similar cytotoxicity profile in WiDr cells as described formerly in 4T1 triple negative breast cancer cells, from the highest to the lowest one is galangin, diosmin, and piperine at the IC 50 of 120 µM (Hasbiyani et al 2021), 389 µM (Musyayyadah et al 2021), and 800 µM (Endah et al 2021), respectively. Accordingly, the most potent among the tested natural compounds is galangin, followed by diosmin and piperine (Figure 2c).…”

“…Additionally, alkaloid piperine found in the most widely used spices, black pepper or other Piper species, is also a promising cancer chemoprevention agent based on its activity on several cancer cell lines (Manayi et al 2018). Reinforcing the mitotic failure as proven in vitro, the bioinformatic analysis confirms that PGV-1 and those above natural compounds target cell cycle protein regulators (Musyayyadah et al 2021;Hasbiyani et al 2021;Endah et al 2021).…”

“…Indeed, PGV-1 is a promising anticancer candidate. (Musyayyadah et al 2021;Hasbiyani et al 2021;Endah et al 2021).…”

“…Numerous compounds from natural sources have been reported to have cytotoxic activities and are conceivable as combination therapy for colorectal cancer (Rejhova et al 2018). Recently, combination of PGV-1 with diosmin, galangin, or piperine (Figure 1) presented promising anti-cancer synergisms in triple negative breast cancer cells (Musyayyadah et al 2021;Hasbiyani et al 2021;Endah et al 2021). Diosmin is a methoxy flavonoid that can be found abundantly in Citrus sp.…”

WITHDRAWN: The Two Mono-Carbonyl Curcumin Analogs, PGV-1 and CCA-1.1: The Chemopreventive Activity Against DMH-Induced Colorectal Cancer Rat and Proteins Target Candidate Involved

“…Two kinds of monocarbonyl curcumin analogs, Pentagamavunone-1 (PGV-1) and Chemopreventive Curcumin Analog 1 (CCA-1.1) (Fig. 1A), were favorable as successor drug for colorectal cancer in several ways: (1) exhibiting irreversible cytotoxic effect in vitro against various cancer cell lines at a lower dose; (2) performing unique target on mitotic phase in the cell cycle; (3) effectively induce cellular senescence and death; (4) suppressing cancer migration in vitro culture system; and (5) inhibiting tumor growth in a xenograft mouse model of leukemia and breast cancer [5][6][7][8][9][10][11]. Both compounds exhibit remarkable cytotoxic activities in various mechanisms such as apoptosis, senescence, autophagy, mitotic arrest, and ROS level generation on colorectal cancer cells.…”