Modulation of tumour pyruvate kinase M2 and suppression of cancer cell proliferation using natural and synthetic antioxidants

被引:1
|
作者
Kapoor, Saumya [1 ]
Kutre, Suraj [2 ]
Joshi, Swarali [3 ]
Goswami, Ashutosh [2 ]
Singh, Amardeep [2 ]
Teja, Parusu Kavya [2 ]
Jadhav, Kishori [2 ]
Tarde, Pooja [2 ]
Jadhav, Rohini [2 ]
Raut, Rohit [2 ]
Solanki, Kajal B. [2 ]
Srivastava, Akshay [4 ]
Chauthe, Siddheshwar K. [2 ]
Sharma, Satyasheel [2 ]
Kate, Abhijeet S. [2 ]
Shard, Amit [1 ]
机构
[1] Natl Inst Pharmaceut Educ & Res Ahmedabad, Dept Med Chem, Gandhinagar 380054, Gujarat, India
[2] Natl Inst Pharmaceut Educ & Res Ahmedabad, Dept Nat Prod, Gandhinagar 382355, Gujarat, India
[3] Natl Inst Pharmaceut Educ & Res Ahmedabad, Dept Biotechnol, Gandhinagar 382355, Gujarat, India
[4] Natl Inst Pharmaceut Educ & Res Ahmedabad, Dept Med Devices, Gandhinagar 380054, Gujarat, India
关键词
Antioxidants; CAL; 27; Cell cycle; Molecular dynamics simulations; OSCC; PKM2; MOLECULAR-DYNAMICS; ALAMAR BLUE; PKM2;
D O I
10.1016/j.molstruc.2024.137751
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
Pyruvate kinase M2 (PKM2), a key glycolytic enzyme, is known to be overexpressed in oral squamous cell carcinoma (OSCC) to cater to the augmented biosynthetic needs of the rapidly proliferating cancerous cells. This brands PKM2 as a pertinent target in OSCC. Numerous antioxidants have previously been identified to modulate PKM2. Herein, we have investigated the anticancer effect of diverse classes of antioxidants on OSCC through modulating PKM2. Screening of antioxidants involved LDH enzyme assay, Alamar assay, apoptosis assay, cellcycle analysis, and RT-PCR studies. Additionally, in silico studies were conducted to gain insights at the protein level. Among 24 antioxidants examined, eugenol (4j) emerged as the most promising PKM2 inhibitor, exhibiting robust PKM2 activity (IC50 = 90.77 +/- 2.4 nM) with potent antiproliferative effects against the CAL 27 cell line (IC50 = 18.42 +/- 1.95 mu M) and no cytotoxicity against NOE cells. Further analysis revealed that eugenol arrested cell growth in the G2 phase of the cell cycle and induced cell death through early apoptosis. Molecular dynamics (MD) simulation studies demonstrated the significant stability of the eugenol-PKM2 complex over 100 ns. Additionally, RT-PCR studies indicated decreased PKM2 expression in cells treated with eugenol. These findings position eugenol as a promising molecule against OSCC, with PKM2 as a potential therapeutic target.
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页数:9
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