Artemisiae Annuae Herba: from anti-malarial legacy to emerging anti-cancer potential

Abstract

Modern medical approaches to cancer treatment face significant obstacles, including limited therapeutic options, narrow drug applicability, and rapid development of drug resistance. Consequently, re-evaluating traditional medicinal plants and natural compounds has emerged as a promising strategy to address this public health issue, particularly amid challenges in developing novel pharmaceuticals. Artemisiae Annuae Herba, a versatile natural drug renowned for its established efficacy against malaria and for other diverse pharmacological activities, is gaining recognition for its anti-cancer potential due to the unique structures and biological effects of its constituents. This review comprehensively outlines the major components of Artemisiae Annuae Herba and their reported anti-cancer activities, beginning with an examination of the molecular structures of the foundational components and an exploration of derivatives of these compounds. Furthermore, through an analysis of observed pharmacological effects, we systematically elucidate the multifaceted influence of Artemisiae Annuae Herba on cancerous tissues, including cell cycle arrest, apoptosis induction, non-apoptotic cell death induction, angiogenesis inhibition, tumor microenvironment remodeling, and immune modulation. Finally, we discuss the feasibility of Artemisiae Annuae Herba in cancer therapy as well as the challenges and unresolved issues that require further investigation. We also consider ways that new drug formulations and routes of administration might overcome these translational hurdles. By synthesizing existing research on applications of Artemisiae Annuae Herba to cancer therapy, this review underscores potentially innovative clinical approaches, ultimately paving the way for the discovery of effective anti-cancer drugs with far-reaching benefits.

Keywords: Artemisiae Annuae Herba; cancer; derivatives; malaria; traditional Chinese medicine.

Figure 1

Historical Timeline of Artemisiae Annuae Herba: Development of Artemisiae Annuae Herba as medicine can be summarized into three periods: ancient age of ignorance, enlightened age of wisdom, and evidence-based age of science. Current research on Artemisiae Annuae Herba is rooted in the enlightenment era of scientific exploration and is moving forward steadily. In the 1960s, the drug was investigated intensely due to the need for anti-malaria treatments, and results were achieved in the 1970s and early 1980s. Other effects of the drug were considered after further promotion of it in the 1990s. Research of Artemisiae Annuae Herba entered the 21st century, with the Nobel Prize serving as a sign of progress.

Figure 2

“World Tree” of Artemisiae Annuae Herba: Artemisiae Annuae Herba has a variety of components as its “roots,” and numerous biological activities and medicinal effects have been developed as its “branches and fruits.” Among the extracts of Artemisiae Annuae Herba, the main compounds are sesquiterpenoids, including artemisinin, artemisinic acid, and artemisitene, along with flavonoids, coumarins, steroids, phenolics, purines, and lipids. It has been developed for A) anti-parasitic, B) anti-viral, C) anti-bacterial and fungal, D) anti-inflammatory, E) anti-obesity, F) anti-osteoporotic, and G) anti-cancer applications.

Figure 3

From molecular structures to mechanisms: Possible anti-cancer mechanisms have been found upon structural analyses of various molecular components of Artemisiae Annuae Herba, and three possible exploration directions have emerged: specific anti-cancer structures, non-specific anti-proliferative structures, and complex regulatory structures. A) Specific anti-cancer structures rely on their unique peroxide bridge, which generates reactive oxygen species under certain conditions to kill tumor cells. B) Non-specific anti-proliferative structures are associated with the cyclic structures and certain functional groups of sesquiterpenoids, influencing cell proliferation through various mechanisms. C) Complex regulatory structures primarily involve diverse polysaccharides and polyphenols, which modulate immune responses and improve the body's anti-cancer capabilities.

Figure 4

From efficacy to mechanisms: Experiments investigating the anti-cancer activities of existing Artemisiae Annuae Herba components were analyzed and summarized, and possible anti-cancer mechanisms were deduced. Improvements to experimental strategies were proposed. At present, the mechanisms can be summarized into six aspects: cell cycle arrest, induction of apoptosis, induction of non-apoptotic cell death, inhibition of angiogenesis, regulation of EMT and inhibition of metastasis, and regulation of immune functions.

Figure 5

Seeking anti-cancer effects among interactions with cell death mechanisms: Artemisiae Annuae Herba components and derivatives can often exert their anti-cancer effects through multiple mechanisms that induce tumor cell death. These mechanisms include A) apoptosis, potentially through activation of caspase pathways (through caspase-3 and -9) or modulation of Bcl-2 family proteins, specifically Bcl-2, BAX and BAK; B) autophagy, influenced by IL-3 and the PI3K/AKT/mTOR pathway; and C) ferroptosis, which is associated with labile iron and the Fenton reaction.

Figure 6

Anti-cancer applications of Artemisiae Annuae Herba: The traditional Chinese medicine Artemisiae Annuae Herba may be utilized in cancer therapies as direct killer drugs and as indirect adjunctive drugs in connection with the application of other Chinese medicines.

Figure 7

Challenges facing the application of Artemisiae Annuae Herba: Although Artemisiae Annuae Herba has bright prospects as cancer treatment, the challenges to its implementation cannot be ignored. The main dilemmas include: A) Challenges of guiding compounds to the cancer site: two strategic approaches are proposed, including synthetic targeting carriers and metabolic precursor utilization; B) Challenges of solubility and delivery: liposomal formulations are a possible solution; C) Challenges of potential risks related to drug metabolism: albumin-bound formulations are proposed as a key strategy; D) Challenges of side effects and safety related to long-term management: multicenter large-scale research must be prioritized and expanded.