Review
Anticancer potential of andrographolide from Andrographis paniculata (Burm.f.) Nees and its mechanisms of action

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Abstract

Ethnopharmacological relevance

Synthetic drugs used for cancer treatment have side effects that may be immunosupressive, can cause liver, kidney and cardiac toxicity, and infertility and ovarian failure, among others. Thus, herbal drugs could be used in the cancer treatment as an adjuvant therapy. Andrographis paniculata (Burm.f.) Nees (AP) is one of the traditional herbs used in different alternative medicinal systems such as Ayurveda, Unani, Chinese, Malayi, Siddha, etc. for the treatment of various disorders and diseases including cancer.

Aim of the study

The aim of writing this review is to highlight the medicinal importance of AP and its main phytoconstituent andrographolide (AG). The main emphasis was given on the anticancer activity of AG, its proposed mechanisms of action, novel approaches used to improve its biopharmaceutical properties with the perspective of evidence-based research, and its development as an adjuvant therapy for cancer treatment in future.

Materials and methods

Literature survey was conducted and research papers were retrieved from different databases such as Pubmed, Google Scholar, ACS, Wiley online library, ScienceDirect, Springer, and Scopus during 1970–2020. Research articles, review articles, and short communications, etc. were used for this purpose. The papers were selected on the basis of exclusion and inclusion criteria.

Results

Different anticancer mechanisms of AG have been reportedly proven such as cell cycle arrest, apoptosis, NF-κβ inhibition, antiangiogenesis, cytokine inhibition, etc. whereas its pharmacokinetic properties showed its highly protein bound nature, Cyt P400 (CYP) inhibition, low aqueous solubility, poor oral bioavailability, etc. Different novel formulations of AG have been investigated to increase its bioavailability for better efficacy.

Conclusion

This review can provide knowledge about the potential applicability of AP or AG as an adjuvant therapy in cancer treatment. Further research is needed before making any conclusion about the efficacy in humans as an adjuvant therapy in cancer.

Introduction

Cancer is a condition in which cells grow abnormally and become potentially capable of invading other parts of the body leading to the group of diseases. As per the GLOBOCON 2018 report on cancer, it is the second major cause of death worldwide with approximately 18.1 million new cases and 9.6 million cancer deaths (excluding non-melanoma skin cancer) (Bray et al., 2018). Until recently, the synthetic drugs used for cancer treatment has some side effects such as ovarian failure and infertility in women, cardiotoxicity, alopecia, weakened immune system, etc. (Meirow and Nugent, 2001; Partridge et al., 2001; Lemieux et al., 2008). There is a need to focus on the alternative treatment (use of traditional medicine), which has least side effect on cancer patients. Plants have been used for thousands of years as a well-known treatment for diseases of any type especially cancer. Plants are sources of biologically active natural products such as flavonoids, phenolics, lactones, and other compounds with reported anticancer activities and capable of enhancing immunity of the patient (Cai et al., 2004; Merfort, 2011).

Andrographis paniculata (Burm.f.) Nees (Kalmegh; Family Acanthaceae) is well-known as the ‘king of bitters’ due to its intensely bitter taste (Thakur et al., 2015). This herb has been used traditionally in various systems of medicine worldwide, since ages in Ayurveda, Unani, Chinese, Malay and Siddha, Japanese, Thai, etc. (Sharma and Sharma, 2018; Mishra et al., 2007). This plant is reported to have diterpenoids, flavonoids, and steroids (Taylor, 1992). The Indian flu epidemic of 1919 is said to be halted by this plant and hence in some cases, it is called as ‘Indian Echinacea’ (Avani and Rao, 2008). Globally, it is found in India, Sri Lanka, Malaysia, Indonesia, Thailand, West Indies, Hong Kong, Brunei, Barbados, Bahamas, etc. (Valdiani et al., 2012). Numerous studies, which have been performed in past ten years reveal its activity as antithrombotic (Thisoda et al., 2006), antiinflammatory (Shen et al., 2006), antiviral (Calabrese et al., 2000; Churiyah et al., 2015), immunostimulatory (See et al., 2002; Churiyah et al., 2015), hypotensive (Zhang and Tan, 1996), anti hyperglycaemic (Zhang and Tan, 2000) and anticancerous (Khan et al., 2018).

Recently, combination chemoprevention is found to be a better and effective approach for cancer management. Several evidences suggest synergistic or additive effects of combination drugs (chemotherapeutic agent with phytoconstituents as an adjuvant drug) in the treatment of cancer in multiple ways like improvement in bioavailability of chemotherapeutic drugs, modification of molecular targets, reduction in effective dose of drug, and reduction in severity of toxicity of chemotherapeutic agent. From ancient times to the modern era, combinatorial therapy for disease management has been used and proven more effective than single drug. Recent studies suggested that AG when given in combination with other chemotherapeutic agents in cancer therapy showed improved efficacy with less side effects (Yuan et al., 2016). Therefore, AG could be a better therapeutic anticancer agent for clinical use. This review article focuses on the use of A. paniculata and its main phytoconstituent andrographolide in the treatment of cancer as an adjuvant therapy. The article touches upon the different aspects related to in vitro cytotoxicity studies and in vivo antitumor studies, different pathways of mechanisms of action, and biopharmaceutical properties to improve its efficacy in cancer therapy among many others.

Section snippets

Method

A literature survey was conducted in which research articles, and reviews or abstracts were retrieved from different databases including Pubmed, Google Scholar, ACS, Wiley online library, ScienceDirect, Springer, and SCOPUS during 1970–2020. Information in English language from research articles, review articles, abstracts, etc. were used for this purpose. The literature search was conducted for each term in all the databases. The terms used were “phytoconstituents of A. paniculata”,

Results

A total of 21,545 research papers were searched for “A. paniculata and andrographolide” using different inclusion criteria, while on the basis of inclusion and exclusion criteria, 21,386 were excluded. Only 159 articles were found to have excellent quality data, which fit under headings and subheadings of the present review. For other individual specific terms, the papers retrieved from each database is combined and its percentage is calculated in total. The percentage of papers searched for

Phytoconstituents of A. paniculata

The leaves, stem, root, and aerial parts of A. paniculata are reported to consist of various phytoconstituents including ent-labdane diterpenoids, flavonoids, quinic acids, xanthones, and noriridoids (Fig. 3). Different solvents were used to extract different types of phytoconstituents, which are summarized in Table 1. AG, a bicyclic diterpene-ϒ- lactone, is the major constituent of AP, and comprises 1% of the herb's dry weight (Talukdar and Dutta, 1969; Joseph and Joseph, 2016). The highest

Conclusion and future perspectives

Cancer is the leading cause of death throughout the globe. Targeting of multiple cellular and molecular pathways by the use of phytochemicals in the modulation of cancer indicates the importance of plants in chemoprevention. AG is a labdane diterpenoid obtained from A. paniculata. The antitumor activity of AG is well-documented due to its reported antiproliferative and antiangiogenic properties. AG exerted its effects in several cancers like breast, cervical, lung, colon, liver, and prostate

Declaration of competing interest

There are no conflict of interest.

Acknowledgements

The authors would like to acknowledge the University Grants Commission of India for providing financial support for this research.

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      Medicinal importance of Andrographis paniculata and its major phyto-constituents viz. andrographolide, deoxyandrographolide has been used for treatment of various pathological conditions has been published by various groups. Particularly the plant extract, the secondary metabolites and their derivatives have been reported to exhibit anti-inflammatory effect [9,10] anti-pyretic activity [11,12] immune-modulatory effects [13] the immune-stimulating effects [14–16], anti-cancer activity [2,17–19] etc. In order to overcome the solubility issue of andrographolide, researchers prefer to protect its hydroxyl groups while doing other semi-synthetic modifications.

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