Saponins in Cancer Treatment: Current Progress and Future Prospects

Abstract

Saponins are steroidal or triterpenoid glycoside that is distinguished by the soap-forming nature. Different saponins have been characterized and purified and are gaining attention in cancer chemotherapy. Saponins possess high structural diversity, which is linked to the anticancer activities. Several studies have reported the role of saponins in cancer and the mechanism of actions, including cell-cycle arrest, antioxidant activity, cellular invasion inhibition, induction of apoptosis and autophagy. Despite the extensive research and significant anticancer effects of saponins, there are currently no known FDA-approved saponin-based anticancer drugs. This can be attributed to a number of limitations, including toxicities and drug-likeness properties. Recent studies have explored options such as combination therapy and drug delivery systems to ensure increased efficacy and decreased toxicity in saponin. This review discusses the current knowledge on different saponins, their anticancer activity and mechanisms of action, as well as promising research within the last two decades and recommendations for future studies.

1. Introduction

Cancer is a group of diseases that is characterized by uncontrolled cell proliferation. This unconstrained cell growth has the potential to invade nearby and distant tissues causing life-threatening complications [1]. Cancer is a global health challenge and is one of the leading causes of death in both develo** and developed countries [2]. An epidemiological study conducted by the World Health Organization (WHO) noted that cancer accounted for the deaths of 7.6 million individuals in 2018, and this figure was expected to double by 2030 [2]. Several treatment options have been sought to treat cancer, the most common of which is chemotherapy. This treatment involves using drugs/chemical agents to destroy rapidly dividing cells and ultimately prevent the spread to other normal cells in the body. Despite the success rate of chemotherapy, patients continue to suffer from several side effects, such as general weakness, fatigue, loss of appetite and infections. In addition, the lack of selectivity and toxicity of Food and Drug Administration (FDA)-approved anticancer drugs has resulted in a significant drawback in the treatment of cancer [3]. Therefore, the search for alternative therapeutic agents in the treatment of cancer is imperative.

Traditional plants contain phytochemical compounds, which are mainly secondary metabolites used by plants to ensure survival and fecundity. Phytochemical compounds of medicinal importance include glucosinolates, alkaloids, triterpenoid, flavonoids, saponins, pigments and tannins. Various studies investigated the use of secondary plant metabolites in traditional medicine. These secondary metabolites displayed different biological activities, such as antimicrobial, anti-inflammatory, cardioprotective, antiviral and anticancer properties. Approximately 60% of anticancer drugs in clinical use and preclinical trials (vinca alkaloids (vinblastine and vincristine), etoposide, paclitaxel, camptothecin, topotecan, irinotecan, curcumin, resveratrol, genistein, allicin, lycopene, diosgenin, beta-carotene, dactinomycin, bleomycin and doxorubicin, paclitaxel and camptothecin) are derived from plants [4,5,6]. These plant-derived anticancer drugs are widely accepted and generally perceived as relatively safe in terms of toxicity. The significant success achieved so far in using natural compounds as chemotherapeutic alternatives has spurred research interest in other secondary metabolites, such as saponins.

Saponins are a class of structurally diverse phytochemicals that are naturally found in higher plants, marine organisms and microorganisms. This group has displayed various pharmacological properties, including anti-inflammatory, antiviral, cardioprotective, immunoregulatory effects and anticancer activity [7,8]. The profound impact of saponins on cancer cells has gained significant research interest in the pharmaceutical sector. These compounds have demonstrated outstanding potential in inhibiting different cancer cells under in vitro and in vivo conditions. Despite the substantial progress made in recent years, the use of saponins as an anticancer agent has faced certain drawbacks, mainly due to their toxicity and poor pharmacokinetic properties. Therefore, this review comprehensively explores the potential of saponins as an anticancer agent by using various mechanisms; this includes the poorly studied pathways, such as those involved in ferroptosis and necroptosis. Furthermore, the current knowledge on the use of saponins as a chemotherapeutic agent and the window of opportunities it presents for future research were also explored.

2. Classification of Saponins

2.1. Sources of Saponins

Saponins can be obtained from two primary sources, namely natural and synthetic. Saponins acquired from natural organisms are termed “natural”, while those derived from the artificial route via laboratory synthesis are known as “synthetic”.

2.1.1. Synthetic Saponins

Saponins are synthesized artificially by derivatization of saponins obtained from natural sources or via de novo synthesis. Various natural saponins, such as oleanane, ursane, lupane, dammarane, cholestane, spirostane, furostane and cardenolide can be synthesized chemically, using numerous techniques [9]. However, there are some drawbacks to these methods, such as low yield, toxicity and stringent reaction conditions. In recent years, the use of Schmidt trichloroacetimidate in activating sugars has shown great potential [10]. Although the mechanisms involving the chemical synthesis of saponins are beyond the scope of this review, it should be noted that the synthetic approach associated with saponin purification from a natural source forestalls the challenge of low yield and purity [11]. Additionally, this methodology allows for a structure-based optimization that will enable the design of saponins equipped with desirable structural features.

2.1.2. Natural Sources of Saponins

Historically, saponins were primarily derived from vegetables and herbs. Saponins from herbs include soapwort, ginseng, ginsenosides, gypenosides, soapberry rhizomes from the Liliaceae, Dioscoreaceae, Agavaceae, Primulaceae, Sapotaceae and Caryophyllaceae families [12,13]. Furthermore, different types of saponins can be isolated within the same plant species. Saponins were initially thought to be endemic to plants but were later discovered in non-plant sources. In the last three decades, marine organisms have been identified as significant sources of saponins. More specifically, organisms belonging to the phylum Echinodermata are rich sources of saponins. Tian et al. identified three groups of saponins (asterosaponins, cyclic glycosides and polyhydroxysteroidal glycosides) in starfish and sea cucumbers [14].

2.2. Classification Based on the Structure

A typical saponin molecule is made up of distinct structural components consisting of an isoprenoid unit and a sugar residue. The former is referred to as the aglycone component, while the latter is called glycone. Acid hydrolysis of the glycosidic bond between glycone and aglycone of saponins can be used to separate these structural units. The biological activities of saponins are due to their unique structure and amphiphilic nature. It consists of a hydrophilic sugar moiety and a hydrophobic genin (called sapogenin). Additionally, aglycones may possess steroids or triterpenes structure, which is used to classify saponins.

Triterpenoid saponins (basic) consist of four or five rings, with a 30-carbon backbone structure derived from 2,3-oxidosqualene [15]. The pentacyclic triterpenoids are the most abundant in plants, and they include oleananes, lupanes, ursanes and derivatives (such as saikosaponins) (Figure 1).

The less common tetracyclic triterpenoid saponins are dammaranes and their derivatives (including ginsenosides), while the steroidal sapogenins are 27-carbon sugar conjugates of steroids consisting of a five- or six-ring skeleton known as spirostane and furostane, respectively. These include dioscin, diosgenin, polyphyllin D, timosaponin AII, cardenolide and cholestane (Figure 2).

Saponins also differ in structural composition, linkage and the number of sugar chains. Usually, the sugar chain may consist of one or more monosaccharide residues attached at C-3 [16]. Based on the number of sugar residues, saponins are classified as monodesmodic, bidesmodic and polydesmodic, if they contain one, two and more than two sugar residues, respectively. Saponins are also named based on the nature of the sugar residue present on their chain. Glucose containing saponins are regarded as glucosides, while galactose containing saponins are galactosides.

3. Anticancer Mechanisms of Saponin

The anticancer activities of saponins include anti-proliferation, anti-metastasis, anti-angiogenesis and reversal of multidrug resistance (MDR). These effects are brought about by induction of apoptosis, promotion of cell differentiation, immune-modulatory effects, bile acid–binding and amelioration of carcinogen-induced cell proliferation [17]. Different molecular mechanisms are involved in the anticancer activity of saponins (

Table 1. Anticancer activities of saponins and sapogenins.

Compound	Cells/Tissue Type	Molecular Target	References
Diosgenin	MCF-7, breast cancer	The activation of p53, disruption of intracellular Ca2+ homeostasis, generation of ROS and caspase activation	[21,22]
Dioscin	Leukemia, lung cancer, gastric carcinoma, hepatocellular carcinoma, cervical cancer, breast cancer	Upregulates FADD, p53, Bid and Bax. Downregulates CDK2,Bcl-2, Clap-1 and Mcl-1	[23,24,25]
Polyphyllin D	Ovarian cancer, cervical cancer, breast cancer, glioblastoma, glioma	Upregulates p53, p21, PDI and JNX. Downregulates CDK1, Bcl-2, HIF- and VEGF	[26,27,28,29]
Oleandrin	Pancreatic cancer, prostate cancer, breast cancer, lymphoma, melanoma, osteosarcoma	Upregulates Akt, ERK and ROS. Downregulates NF-κB, MAPK, JNK, pS6, p4EPB1, PI3K/Akt and mTOR.	[30]
Ginsenoside Rg3	Lung cancer, esophageal carcinoma, gastric cancer, colon cancer, hepatoma, renal cancer, bladder cancer, breast cancer, ovarian cancer, prostate cancer and melanoma	Upregulates p63,p21, Bax and Smac Downregulates VEGF, p38 and P13K,	[17]
Ginsenoside Rh2	Leukemia, colon cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer	Upregulates p53, p21, p27 and p16 Downregulates AKT, CDK4, CDK6 and AP-1.	[17]
Saikosaponin A	Hepatocellular carcinoma, breast cancer, colon cancer	Upregulates p15, p16, ERK and cleaved-PARP Downregulates Bcl-2, XIAP, Clap2 and Pgp	[31]
Saikosaponin D	Lung cancer, hepatocellular carcinoma, prostate cancer, thyroid cancer	Upregulates p53, p21, Fas and Bax, Downregulates Bcl-2, CDK2, COX-2 and STAT3	[32]
Polyphyllin D	Human non-small-cell lung cancer NCI-H460 cell line.	ER stress-mediated apoptosis, induction of tumor suppressor p53, disruption of mitochondrial membrane and activation of caspase-9 and caspase-3	[33]
Timosaponin AIII (TAIII)	Breast, prostate, HepG2, pancreatic and osteosarcoma cancer cells. PANC-1 cell xenograft nude mice model	ER stress induction, activation of caspase-3, downregulation of Bcl-2, X-linked inhibitor of apoptosis protein (XIAP), Mcl-1 and IAPs, induction of cytochrome c and stimulation of caspases 3, 7, 8 and 9	[34,35,36]
OSW-1(3β,16β,17α-trihydroxycholest-5-en-22-one16- O -(2- O -4-methoxybenzoyl-β- D -xylopyranosyl)-(1→3)-(2- O -acetyl-α- L -arabinopyranoside)	Leukemia cancer and pancreatic cancer cells	Mitochondria membrane permeabilization. Intrinsic apoptosis. Calcium-dependent GRP78 (survival factor) cleavage. Binding to oxysterol binding protein to activate the Golgi stress response leading to apoptosis	[37,38,39]

). It should be noted that the mechanism of anticancer action of saponins is strongly related to the nature of the structural moieties, including the aglycone moiety, the length and linkage of the glycosidic chain, the presence of a functional carboxylic group on the aglycone chain, the number of sugar molecules and hydroxyl group, position of the hydroxyl group, stereo-selectivity and the type of sugar molecule on the glycine chain [18,19,20]. This section considers the critical processes in cancer-cell development and how different saponins help to inhibit cancer at various stages.

3.1. Chemoprevention and Saponin

Chemoprevention is the use of a chemotherapeutic agent to halt or restrict tumor development before the onset of cellular invasion. The chemopreventive action of saponins involves anti-inflammation, redox potential modulation and cell proliferation inhibition through different pathways (Figure 3).

3.1.1. Anti-Inflammatory Activity

The immune system triggers an inflammatory response to foreign invaders as part of the body’s defense mechanism. Nonetheless, excessive or chronic inflammation is associated with different pathological conditions, one of which is cancer [40]. Due to the link between cancer and inflammation, several anti-inflammatory drugs help to decrease the incidence of cancer. Most inflammatory drugs have been designed to selectively target proteins, such as nuclear factor Kappa B (NF-κB), IL-6/STAT3, IL-23/Th-17 and cyclooxygenase-2 (Cox-2), which are responsible for inflammatory response. Similar to other anti-inflammatory drugs, some saponins can regulate the expression of a number of these proteins.

The inducible transcription factor, NF-κB, stimulates the expression of pro-inflammatory and pro-survival genes. These can be activated via a canonical pathway involving TNF-α, T-cell and B-cell receptors. Triggering this protein in cancer cells leads to activation of cell-cycle proteins, metalloproteinase and apoptotic proteins. Reports have identified saponins that inhibit NF-κB and inhibitory kappa B kinase (IKK). For instance, Paris saponin II, a steroidal saponin, inhibits IKK-b, a protein involved in the canonical pathway of NF-κB activation, leading to cell-cycle arrest and apoptosis activation [41]. Moreover, Raddeanin A, a triterpenoid, inactivates NF-κB by preventing the phosphorylation of Ikkb-α. A study by ** saponin derived anticancer agents in the near future.

5. Concluding Remarks

The overwhelming evidence from several studies has shown the different anticancer effects of saponins. Previous research has largely linked the anticancer action to membrane permeabilization (which leads to apoptosis); however, more recently discovered saponins have demonstrated enhanced chemopreventive and chemotherapeutic action, utilizing different cytotoxic pathways. Some of these saponins have been demonstrated to have antioxidant properties as well as the ability to control the expression of proteins involved in cell cycle, cancer progression and metastasis. Despite the progress made so far in the use of saponin for cancer treatment, toxicity and low bioavailability remain significant obstacles. Moreover, another difficulty is the fact that the role of diverse saponin scaffolds in anticancer action is unknown, making drug optimization challenging. Combination therapy and more efficient drug delivery technologies, both of which have been used in saponins research have shown the best promise so far. The evidence from these studies, on the other hand, is primarily from in vitro investigations and is quite limited. Further structure-dependent activity and preclinical and clinical studies are therefore essential to ensure the translation of saponin based anticancer drugs from bench to bedside.