Anti-Cancer Agent: The Labdane Diterpenoid-Andrographolide

Abstract

In spite of the progress in treatment strategies, cancer remains a major cause of death worldwide. Therefore, the main challenge should be the early diagnosis of cancer and the design of an optimal therapeutic strategy to increase the patient's life expectancy as well as the continuation of the search for increasingly active and selective molecules for the treatment of different forms of cancer. In the recent decades, research in the field of natural compounds has increasingly shifted towards advanced and molecular level understandings, thus leading to the development of potent anti-cancer agents. Among them is the diterpene lactone andrographolide, isolated from Andrographis paniculata (Burm.f.) Wall. ex Nees that showed shows a plethora of biological activities, including not only anti-cancer activity, but also anti-inflammatory, anti-viral, anti-bacterial, neuroprotective, hepatoprotective, hypoglycemic, and immunomodulatory properties. Andrographolide has been shown to act as an anti-tumor drug by affecting specific molecular targets that play a part in the development and progression of several cancer types including breast, lung, colon, renal, and cervical cancer, as well as leukemia and hepatocarcinoma. This review comprehensively and systematically summarized the current research on the potential anti-cancer properties of andrographolide highlighting its mechanisms of action, pharmacokinetics, and potential side effects and discussing the future perspectives, challenges, and limitations of use.

Keywords: angiogenesis; apoptosis; autophagy; cancer; enhanced radio-sensitivity; mechanism of action.

Figure 1

The chemical configuration of andrographolide and its derivatives that are used commercially in clinical practices. Reproduced with permission from Zhang et al. [21], licensed content publisher—Elsevier.

Figure 2

A. paniculata and its main compound andrographolide.

Figure 3

The chemical structure of the characteristic C-3 and C-19 esters of the andrographolide (1) compound with anti-cancer activity; (a) & (b) are the most active compounds with GI₅₀ values of 1.46–9.19 μM against A549 (lung cancer), DU145 (prostate cancer), KB (oral cancer), and KB-Vin tumor cells. Reproduced with permission from Kumar et al. [33], 2020, licensed content publisher—Elsevier.

Figure 4

The principal mechanisms of action of andrographolide as an anti-cancer agent.

Figure 5

A pictorial representation of the anti-cancer mechanism of action of andrographolide. Reproduced with permission from Zeng et al. [36].

Figure 6

Pictorial representation of action mechanism of AGS-30, an andrographolide derivative, suppressing the tumor angiogenesis process. Reproduced with permission from Li et al. [83].

Figure 7

Pictorial representation of mechanism of action of inhibition of tumor-derived IL-8-induced angiogenesis by andrographolide in the tumor microenvironment. (A) Andrographolide mediates inhibition of TNF-α-induced IL-8 through the inhibition of NADPH oxidase/ROS/NF-κB and Src/MAPKs/AP-1signaling pathways in the HCT116 colorectal cancer cells. (B) Secretion of the IL-8 from cancer cells increases the multiplication of endothelial cells to endorse the angiogenesis process in the tumor microenvironment. Andrographolide obstructs the countenance of tumor-derived IL-8, thus preventing angiogenesis in the tumor microenvironment. Reproduced with permission from Yuan et al. [116]. Copyright © 2023, American Chemical Society.

Figure 8

(A,B) Regulation of JAK-STAT signaling by andrographolide. Andrographolide effectively inhibited JAK1, JAK2, and STAT3. (C) Andrographolide inhibited phosphorylation of STAT3 on the 705th tyrosine and 727th serine. Adopted from Farooqi et al. [120], under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/), 2020. Licensee MDPI, Basel, Switzerland.