Patchouli alcohol induces G <sub>0</sub> /G <sub>1</sub> cell cycle arrest and apoptosis in vincristine‐resistant non‐small cell lung cancer through ROS‐mediated DNA damage

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Abstract

Background

Lung cancer, especially non‐small cell lung cancer (NSCLC), is one of the leading causes of cancer‐related deaths worldwide. Vincristine (VCR) is a chemotherapeutic agent for lung cancers; however, its effectiveness is limited by side effects and the development of drug resistance. Patchouli alcohol (PA), from Pogostemon cablin extract, is known to possess anti‐inflammatory and anticancer properties. In this study, we investigated the role of PA in inducing reactive oxygen species (ROS)‐mediated DNA damage in A549 and VCR‐resistant A549/V16 NSCLC cells.

Methods

The anticancer potential of PA was studied using the MTT assay, colony formation, flow cytometry analysis, western blotting, DCFDA staining, immunofluorescence staining, and TUNEL assay techniques.

Results

The intracellular ROS levels were enhanced in PA‐treated cells, activating the CHK1 and CHK2 signaling pathways. PA further inhibited proliferation and colony‐forming abilities and induced cell cycle arrest at the G ₀/G ₁ phase by regulating p53/p21 and CDK2/cyclin E1 expression. Moreover, PA increased the percentage of cells in the subG ₁ phase and induced apoptosis by activating the Bax/caspase‐9/caspase‐3 intrinsic pathway. In addition, drug resistance (p‐glycoprotein) and cancer stem cell (CD44 and CD133) markers were downregulated after PA treatment. Furthermore, combining PA and cisplatin exhibited synergistic inhibitory activity in A549 and A549/V16 cells.

Conclusions

PA induced ROS‐mediated DNA damage, triggered cell cycle arrest and apoptosis, attenuated drug resistance and cancer stem cell phenotypes, and synergistically inhibited proliferation in combination with cisplatin. These findings suggest that PA has the potential to be used for the treatment of NSCLC with or without VCR resistance.

Abstract

Results indicated that patchouli alcohol (PA) enhanced the expression of intracellular reactive oxygen species (ROS) and oxidative DNA damage maker 8‐OHdG, resulting in induction of cell cycle G ₀/G ₁ arresting as well as apoptosis in vincristine (VCR)‐resistant non‐small cell lung cancer (NSCLC) A549/V16 cells. The findings of the present study suggested that PA may be a promising therapeutic agent or adjuvant for the treatment of NSCLC with VCR resistance.

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Most cited references 48

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Reactive oxygen species (ROS) as pleiotropic physiological signalling agents

Helmut Sies, Dean Jones (2020)

'Reactive oxygen species' (ROS) is an umbrella term for an array of derivatives of molecular oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to molecular damage, denoted as 'oxidative distress'. Here we focus on ROS at physiological levels and their central role in redox signalling via different post-translational modifications, denoted as 'oxidative eustress'. Two species, hydrogen peroxide (H2O2) and the superoxide anion radical (O2·-), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiological levels in the nanomolar range, H2O2 is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addition, several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids. Recent methodological advances permit the assessment of molecular interactions of specific ROS molecules with specific targets in redox signalling pathways. Accordingly, major advances have occurred in understanding the role of these oxidants in physiology and disease, including the nervous, cardiovascular and immune systems, skeletal muscle and metabolic regulation as well as ageing and cancer. In the past, unspecific elimination of ROS by use of low molecular mass antioxidant compounds was not successful in counteracting disease initiation and progression in clinical trials. However, controlling specific ROS-mediated signalling pathways by selective targeting offers a perspective for a future of more refined redox medicine. This includes enzymatic defence systems such as those controlled by the stress-response transcription factors NRF2 and nuclear factor-κB, the role of trace elements such as selenium, the use of redox drugs and the modulation of environmental factors collectively known as the exposome (for example, nutrition, lifestyle and irradiation).

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Drug combination studies and their synergy quantification using the Chou-Talalay method.

Ting-Chao Chou (2010)

This brief perspective article focuses on the most common errors and pitfalls, as well as the do's and don'ts in drug combination studies, in terms of experimental design, data acquisition, data interpretation, and computerized simulation. The Chou-Talalay method for drug combination is based on the median-effect equation, derived from the mass-action law principle, which is the unified theory that provides the common link between single entity and multiple entities, and first order and higher order dynamics. This general equation encompasses the Michaelis-Menten, Hill, Henderson-Hasselbalch, and Scatchard equations in biochemistry and biophysics. The resulting combination index (CI) theorem of Chou-Talalay offers quantitative definition for additive effect (CI = 1), synergism (CI 1) in drug combinations. This theory also provides algorithms for automated computer simulation for synergism and/or antagonism at any effect and dose level, as shown in the CI plot and isobologram, respectively.

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Author and article information

Contributors

Chih‐Yen Hsiao:

ORCID: https://orcid.org/0000-0003-1199-6977

04504@cych.org.tw

Nu‐Man Tsai:

ORCID: https://orcid.org/0000-0002-2629-1833

numan@csmu.edu.tw

Journal

Journal ID (nlm-ta): Thorac Cancer

Journal ID (iso-abbrev): Thorac Cancer

Journal ID (doi): 10.1111/(ISSN)1759-7714

Journal ID (publisher-id): TCA

Title: Thoracic Cancer

Publisher: John Wiley & Sons Australia, Ltd (Melbourne )

ISSN (Print): 1759-7706

ISSN (Electronic): 1759-7714

Publication date (Electronic): 30 May 2023

Publication date Collection: July 2023

Volume: 14

Issue: 21 ( doiID: 10.1111/tca.v14.21 )

Pages: 2007-2017

Affiliations

[ ¹ ] Division of Pulmonary Medicine, Department of Internal Medicine Ditmanson Medical Foundation Chia‐Yi Christian Hospital Chia‐Yi Taiwan, ROC

[ ² ] Department of Medical Laboratory and Biotechnology Chung Shan Medical University Taichung Taiwan, ROC

[ ³ ] Institute of Medicine, Chung Shan Medical University Taichung Taiwan, ROC

[ ⁴ ] Division of Nephrology, Department of Internal Medicine Ditmanson Medical Foundation Chia‐Yi Christian Hospital Chia‐Yi Taiwan, ROC

[ ⁵ ] Clinical Laboratory Chung Shan Medical University Hospital Taichung Taiwan, ROC

[ ⁶ ] Department of Life‐and‐Death Studies Nanhua University Chiayi Taiwan, ROC

Author notes

[*] [* ] Correspondence

Chih‐Yen Hsiao, Division of Nephrology, Department of Internal Medicine, Ditmanson Medical Foundation Chia‐Yi Christian Hospital, Chia‐Yi 60002, Taiwan, ROC.

Email: 04504@ 123456cych.org.tw

Nu‐Man Tsai, Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, No.110, Sec. 1, Jianguo N. Rd., Taichung City 40201, Taiwan, ROC.

Email: numan@ 123456csmu.edu.tw

Author information

Chi‐Yen Liang https://orcid.org/0000-0002-3008-1134

Kai‐Fu Chang https://orcid.org/0000-0003-1640-1960

Ya‐Chih Huang https://orcid.org/0000-0001-9990-7494

Xiao‐Fan Huang https://orcid.org/0000-0001-5164-5966

Gwo‐Tarng Sheu https://orcid.org/0000-0002-1299-3375

Chih‐Yen Hsiao https://orcid.org/0000-0003-1199-6977

Nu‐Man Tsai https://orcid.org/0000-0002-2629-1833

Article

Publisher ID: TCA14982

DOI: 10.1111/1759-7714.14982

PMC ID: 10363793

PubMed ID: 37249164

SO-VID: eecb9bf6-0f02-4125-9750-3a2a4574c7b3

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date revision received : 11 May 2023

Date received : 26 March 2023

Date accepted : 16 May 2023

Page count

Figures: 8, Tables: 2, Pages: 11, Words: 7520

Funding

Funded by: Ditmanson Medical Foundation Chia‐Yi Christian Hospital

Award ID: R111‐12

Funded by: Ministry of Science and Technology, Taiwan , doi 10.13039/501100004663;

Award ID: MOST 109‐2320‐B‐040‐012

Award ID: MOST 110‐2320‐B‐040‐006

Award ID: MOST 111‐2320‐B‐040‐022

Custom metadata

source-schema-version-number 2.0

cover-date July 2023

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.3.2 mode:remove_FC converted:24.07.2023

Keywords: apoptosis,non‐small cell lung cancer,patchouli alcohol,ros,vincristine resistance

Data availability:

Keywords: apoptosis, non‐small cell lung cancer, patchouli alcohol, ros, vincristine resistance