Onosma bracteata Wall. induces G0/G1 arrest and apoptosis in MG-63 human osteosarcoma cells via ROS generation and AKT/GSK3β/cyclin E pathway

Abstract

Onosma bracteata Wall. (Boraginaceae), commonly known as “gaozaban” is a highly valuable medicinal herb, useful in the treatment of body swellings, abdominal pain, eye-related problems, fever, and urinary calculi. The present study was performed to investigate the antioxidant properties of extract/fractions, viz. ethanol (Obeth) extract, hexane (Obhex) fraction, chloroform (Obcl) fraction, ethyl acetate (Obea) fraction, butanol (Obbu) fraction, and aqueous (Obaq) fraction isolated from O. bracteata. Obea fraction showed stronger free radical quenching ability in various antioxidant assays, as compared to the other fractions. Obea fraction with effective free radical-scavenging properties was further evaluated for the antiproliferative activity against human osteosarcoma MG-63, human neuroblastoma IMR-32, and human lung cancer A549 cell lines using MTT assay. Obea fraction showed strong cytotoxicity with GI50 value of 88.56, 101.61, and 112.7 μg/ml towards MG-63, IMR-32, and A549 cells respectively. Mechanistic studies revealed that Obea fraction in osteosarcoma MG-63 cells increased reactive oxygen species (ROS) level and reduced mitochondrial membrane potential. In the presence of Obea, the cells were found to be arrested in the G0/G1 phase in a dose-dependent manner which is also confirmed by the enhancement in the early apoptotic cell population in flow cytometer analysis. Western blotting demonstrated the decrease in expression of p-NFκB, COX-2, p-Akt, and Bcl-xL, whereas upregulation was observed in the expression of GSK-3β, p53, caspase-3, and caspase-9 proteins. RT-qPCR studies revealed downregulation of Bcl-2, cyclin E, CDK2, and mortalin gene expression and upregulation in the expression of p53 genes. The antioxidant and cytotoxic potential of Obea was attributed to the presence of catechin, kaempferol, onosmin A, and epicatechin, as revealed by HPLC analysis. This is the first report regarding the antiproliferative potential of O. bracteata against osteosarcoma.

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Data availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.

Abbreviations

Apaf-1:

Apoptotic protease activating factor 1

AO/EtBr:

Acridine orange/ethidium bromide

Bcl-2:

B cell lymphoma 2

CHO:

Chinese hamster ovary

COX-2:

Cyclooxygenase-2

CO2 :

Carbon dioxide

EA:

Early apoptosis

EDTA:

Ethylenediaminetetraacetic acid

GSK:

Glycogen synthase kinase

LA:

Late apoptosis

L:

Live

MG-63:

Human osteosarcoma cells

MMP:

Mitochondria membrane potential

N:

Necrotic

NFκB:

Nuclear factor kappa B

p-Akt:

Phosphorylated-Akt

PVDF:

Polyvinylidene fluoride

PAGE:

Polyacrylamide gel electrophoresis

PBS:

Phosphate-buffered saline

RT-qPCR:

Quantitative real-time polymerase chain reaction

ROS:

Reactive oxygen species

Rh123:

Rhodamine123

rpm:

Revolutions per minute

SDS:

Sodium dodecyl sulfate

SEM:

Scanning electron microscopy

WB:

Western blotting

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Acknowledgments

The authors thankful to University Grants Commission (UGC) - Basic Scientific Research (BSR), DST-FIST (Grant No. SR/FST/LSI-691/2016 (C)) program for providing financial assistance. The authors also acknowledge UGC, New Delhi, for the instrumentation facility under UGC-DRS V (Grant No. F4-13/2015/DRS-II), CPEPA, RUSA 2.0 scheme, UPE program, and the Centre of Emerging Life Sciences, Guru Nanak Dev University, Amritsar (India), for providing the required support and facilities.

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Ajay Kumar: conceptualization, methodology, validation, writing—original draft, investigation, software. Sandeep Kaur: conceptualization, investigation. Kritika Pandit: investigation, formal analysis. Varinder Kaur: investigation, formal analysis. Sharad Thakur: investigation, Satwinderjeet Kaur: supervision, validation, methodology, conceptualization, validation, writing—original draft. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Satwinderjeet Kaur.

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Kumar, A., Kaur, S., Pandit, K. et al. Onosma bracteata Wall. induces G0/G1 arrest and apoptosis in MG-63 human osteosarcoma cells via ROS generation and AKT/GSK3β/cyclin E pathway. Environ Sci Pollut Res (2020). https://doi.org/10.1007/s11356-020-11466-9

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Keywords

  • Onosma bracteata
  • Antiproliferative
  • Antioxidant
  • Cell cycle arrest
  • Apoptosis
  • Osteosarcoma
  • ROS