Sadegh Rajabi1, Shokoofe Noori2, Mohammad Reza Ashrafi3, Mahsa Azami Movahed4, Shabnam Farzaneh4, Afshin Zarghi5. 1. Traditional Medicine and Materia Medica Research Center (TMRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Shnoori@sbmu.ac.ir. 3. Department of Biochemistry, Afzalipoor Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran. 4. Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 5. Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. zarghi@sbmu.ac.ir.
Abstract
BACKGROUND: FMSP is a synthesized ferrocene derivative with anti-cancer characteristics on tumor cells. Naringenin is a polyphenolic flavonoid with anti-tumor ability. METHODS: Cell viability and proliferation of two cancer cells and a normal cell line after treatment with these agents were determined with MTT assay. To predict the possible interaction between calmodulin (CaM) and FMSP and naringenin, docking studies were performed. By using fluorescence emission spectra, the effects of FMSP and naringenin on CaM structure and activity were studied. CaM-dependent activation of phosphodiesterase 1 (PDE1) by FMSP in relation to naringenin and their combination were compared. Effects of these compounds on PDE1 inhibition, cAMP accumulation, and cAMP-dependent protein kinase A (PKA) activation were assayed. RESULTS: The combination of FMSP and naringenin had more inhibitory effects on CaM structure than FMSP and naringenin alone. Results of docking analyses also confirmed efficient interaction of the two compounds with a hydrophobic pocket of calmodulin active site. Kinetic analyses of these agents' interaction with CaM showed FMSP and naringenin both competitively inhibited PDE1 activation without changing the Vmax parameter. FMSP and naringenin synergistically increased Km values at a higher level compared to FMSP or naringenin alone. The combination of these two agents also had more cytotoxic effects on cancer cells than FMSP alone. CONCLUSIONS: It was shown that mechanism of proliferation inhibition in both cancer cells by these compounds is based on CaM and consequent PDE inhibition followed by intracellular cAMP level elevation and increased PKA activity in a dose-dependent manner.
BACKGROUND: FMSP is a synthesized ferrocene derivative with anti-cancer characteristics on tumor cells. Naringenin is a polyphenolic flavonoid with anti-tumor ability. METHODS: Cell viability and proliferation of two cancer cells and a normal cell line after treatment with these agents were determined with MTT assay. To predict the possible interaction between calmodulin (CaM) and FMSP and naringenin, docking studies were performed. By using fluorescence emission spectra, the effects of FMSP and naringenin on CaM structure and activity were studied. CaM-dependent activation of phosphodiesterase 1 (PDE1) by FMSP in relation to naringenin and their combination were compared. Effects of these compounds on PDE1 inhibition, cAMP accumulation, and cAMP-dependent protein kinase A (PKA) activation were assayed. RESULTS: The combination of FMSP and naringenin had more inhibitory effects on CaM structure than FMSP and naringenin alone. Results of docking analyses also confirmed efficient interaction of the two compounds with a hydrophobic pocket of calmodulin active site. Kinetic analyses of these agents' interaction with CaM showed FMSP and naringenin both competitively inhibited PDE1 activation without changing the Vmax parameter. FMSP and naringenin synergistically increased Km values at a higher level compared to FMSP or naringenin alone. The combination of these two agents also had more cytotoxic effects on cancer cells than FMSP alone. CONCLUSIONS: It was shown that mechanism of proliferation inhibition in both cancer cells by these compounds is based on CaM and consequent PDE inhibition followed by intracellular cAMP level elevation and increased PKA activity in a dose-dependent manner.
Authors: Maxine J Roberts; Lauren T May; Alastair C Keen; Bonan Liu; Terrance Lam; Steven J Charlton; Elizabeth M Rosethorne; Michelle L Halls Journal: Front Pharmacol Date: 2021-04-29 Impact factor: 5.810
Authors: Mariana Miranda Sampaio; Maria Luísa Cordeiro Santos; Hanna Santos Marques; Vinícius Lima de Souza Gonçalves; Glauber Rocha Lima Araújo; Luana Weber Lopes; Jonathan Santos Apolonio; Camilo Santana Silva; Luana Kauany de Sá Santos; Beatriz Rocha Cuzzuol; Quézia Estéfani Silva Guimarães; Mariana Novaes Santos; Breno Bittencourt de Brito; Filipe Antônio França da Silva; Márcio Vasconcelos Oliveira; Cláudio Lima Souza; Fabrício Freire de Melo Journal: World J Clin Oncol Date: 2021-02-24