title: Anti-leukemic, anti-lung, and anti-breast cancer potential of the microbial polyketide 2, 4-diacetylphloroglucinol (DAPG) and its interaction with the metastatic proteins than the antiapoptotic Bcl-2 proteins.
abstract: The microbial polyketide, 2, 4-diacetylphloroglucinol (DAPG), exhibited a broad-spectrum of anti-leukemic, anti-lung, and anti-breast cancer properties. The aim of the present investigation was to study the interactive potentials of DAPG with the metastatic proteins such as MMP-2, MMP-9, and NF-κB and antiapoptotic Bcl-2 family proteins such as Bcl-2, Bcl-w, and Bcl-xL through in silico interaction and in vitro studies. The in silico modeling predicted high interactions of DAPG with the metastatic proteins, especially MMP-2, MMP-9, and NF-κB with the glide score of -7.028, -6.304, and -5.231, respectively. Similarly, the DAPG had weak interactions with the antiapoptotic Bcl-2, Bcl-w, and Bcl-xL with the glide score of -4.505, -3.839, and -4.003, respectively. The interaction studies further revealed the inhibition of MMP-2, MMP-9, and NF-κB activities with the low IC50 concentration of 5.82 ± 1.6, 6.74 ± 1.2, and 10.7 ± 1.5 μM respectively, in the presence of DAPG. Similarly, DAPG inhibited the Bcl-2, Bcl-xL and Bcl-w activities with the high IC50 concentration of 29.8 ± 1.9, 85.9 ± 2.7, and 97.4 ± 1.5 μM, respectively. These results correlate with the relatively high IC50 concentration of 16.3 ± 1.76, 7.67 ± 0.78, and 10.7 ± 0.96 μM in the Bcl-2-overexpressing HL-60, K562 and Raji leukemic cells than the metastatic A549 and MDA MB-231 cancer cells with the low IC50 concentration of 0.06 ± 0.02 and 0.08 ± 0.01 μM, respectively, compared to the healthy, human embryonic kidney (HEK-293) cells with the high IC50 concentration of 54.7 ± 1.43 μM. In summary, the affinity of DAPG with proteins are in the order of MMP-2 > MMP-9 > NF-κB > Bcl-2 > Bcl-xL > Bcl-w. Results presented in this study confirmed the high interaction of DAPG with the metastatic proteins than the antiapoptotic Bcl-2 family proteins.
authors.affiliation: Department of Biotechnology, School of Life Science, Pondicherry University, Pondicherry, 605014, India.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Veena
authors.affiliation: Department of Biotechnology, School of Life Science, Pondicherry University, Pondicherry, 605014, India.
authors.forename: Kamaraj
authors.initials: K
authors.lastname: Kennedy
authors.affiliation: Centre for Bioinformatics, School of Life Science, Pondicherry University, Pondicherry, India.
authors.forename: Pragna
authors.initials: P
authors.lastname: Lakshmi
authors.affiliation: Centre for Bioinformatics, School of Life Science, Pondicherry University, Pondicherry, India.
authors.forename: R
authors.initials: R
authors.lastname: Krishna
authors.affiliation: Department of Biotechnology, School of Life Science, Pondicherry University, Pondicherry, 605014, India. puns2005@gmail.com.
authors.forename: N
authors.initials: N
authors.lastname: Sakthivel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D006801:Humans; D007938:Leukemia / Q000473:pathology / Q000517:prevention & control*; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control*; D062105:Molecular Docking Simulation; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism*; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C059817:2,4-diacetylphloroglucinol; D010696:Phloroglucinol
keywords: Antiapoptotic Bcl-2 family members; DAPG; In silico interaction studies; In vitro validation studies; Metastatic proteins
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