The Anticancer Potential of Quassinoids-A Mini-Review

Cai Lu , Si-Nan Lu , Di Di , Wei-Wei Tao , Lu Fan , Jin-Ao Duan , Ming Zhao , Chun-Tao Che

Engineering ›› 2024, Vol. 38 ›› Issue (7) : 34 -47.

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Engineering ›› 2024, Vol. 38 ›› Issue (7) :34 -47. DOI: 10.1016/j.eng.2023.11.022
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The Anticancer Potential of Quassinoids-A Mini-Review
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Abstract

The anticancer potential of quassinoids has attracted a great deal of attention for decades, and scientific data revealing their possible applications in cancer management are continuously increasing in the literature. Aside from the potent cytotoxic and antitumor properties of these degraded triterpenes, several quassinoids have exhibited synergistic effects with anticancer drugs. This article provides an overview of the potential anticancer properties of quassinoids, including their cytotoxic and antitumor activities, mechanisms of action, safety evaluation, and potential benefits in combination with anticancer drugs.

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Keywords

Quassinoid / Anticancer potential / Antiproliferative mechanism / Safety evaluation / Synergistical combination with anticancer / drugs

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Cai Lu, Si-Nan Lu, Di Di, Wei-Wei Tao, Lu Fan, Jin-Ao Duan, Ming Zhao, Chun-Tao Che. The Anticancer Potential of Quassinoids-A Mini-Review. Engineering, 2024, 38(7): 34-47 DOI:10.1016/j.eng.2023.11.022

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1. Introduction

Cancer is the second most common cause of death worldwide, accounting for one in four deaths [1]. With rapid global population growth and aging, cancer is expected to become the leading cause of death and the predominant barrier to increasing life expectancy in this century [2]. During the past decades, we have witnessed many innovative discoveries and groundbreaking successes in the efforts to make progress against cancer, even though these have been far from perfect attempts. Currently, for most cancer patients, surgery combined with chemotherapy and/or radiation therapy is the first-line treatment [3]. However, chemotherapy and radiotherapy may cause the patient to suffer from various kinds of pains, serious side-effects, and/or poor quality of life [4]. To address the cancer burden, the development of better prevention strategies, early diagnostic methods, new therapeutic regimens, and good palliative care is needed. The discovery and development of novel, effective, and safe anticancer strategies are thus essential for the continued fight against the disease. As far as chemotherapy is concerned, the search for anticancer compounds continues. Aside from the synthetic approach, natural products (e.g., plant and microbial metabolites) have historically made significant contributions to cancer treatment, and they remain a crucial and promising source of bioactive compounds with therapeutic today [5].

Quassinoids are a small class of highly oxygenated and degraded triterpene lactones found exclusively in plants belonging to the Simaroubaceae family [6]. In the past few decades, among the almost 500 compounds of this class, many have been reported to exhibit broad spectra of biological activities, including potent cytotoxic and antitumor properties [7], [8]. Since the discovery of the clinical potential of bruceantin [9] against breast cancer and melanoma [10], [11] in the 1980s, the antitumor properties of quassinoids have fascinated pharmaceutical and biomedical scientists. We herein provide a summary of the progress of anticancer-related studies on quassinoids in recent decades, including their in vitro and in vivo activities, mechanisms of action, safety evaluation, and potential benefits in combination with clinical anticancer drugs.

2. The anticancer potential of quassinoids

2.1. Cytotoxic and antitumor activities in vitro and in vivo

The available information on the cytotoxic and antitumor activities of quassinoids is summarized in Fig. 1 [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], Table 1 [14], [16], [18], [21], [23], [24], [27], [32], [33], [39], [47], [50], [51], [52], [53], [54], [55], [56], [57], [58], and Table S1 in Appendix A. Below, we provide highlights of some significant results.

Brusatol has attracted burgeoning interest from many pharmaceutical researchers due to its potent antiproliferative effect against several cancer cell lines. In non-small-cell lung cancer (NSCLC) cells, the half-maximal inhibitory concentration (IC50) values of brusatol were found to be 0.035, 0.047, 0.028, and 0.140 μmol·L−1 in PC9, H1650, A549, and HCC827 cells, respectively. In particular, the cytotoxic potency of brusatol against PC9 and H1650 cells was found to be comparable to that of paclitaxel [12]. In addition to its effect on lung cancer cells, brusatol is known to exhibit higher potency than camptothecin, with IC50 values of 0.36 and 0.10 μmol·L−1 against the pancreatic cancer PANC‐1 and SW1990 cell lines, respectively [13].

Bruceine A significantly inhibited the growth of a panel of pancreatic cancer cells (MIA PaCa-2, SW1990, PANC-1, and AsPC-1), but it was relatively non-toxic to the control cells (HPED6-C7) [14]. At the same time, it seemed to have higher selectivity toward MIA PaCa-2 cells (IC50 29 nmol·L−1) than toward other tumor types (MCF-7, A549, and HepaRG) [14].

Other quassinoids have also exhibited cytotoxic activities against pancreatic cancer cells. For example, picrajavanicins H-M, isolated from Picrasma javanica bark, displayed potent and selective antiproliferative activity against PANC-1 cells, with IC50 values ranging from 3.25 to 17.41 µmol·L−1 [15]. Compared with the current first-line drugs gemcitabine (GEM) and 5-fluorouracil (5-FU), bruceine D displayed higher cytotoxic potency against pancreatic cancer Capan-1 (IC50 1.95 μmol·L−1), PANC-1 (IC50 7.33 μmol·L−1), and Capan-2 (IC50 2.80 μmol·L−1) cells, yet it was much less cytotoxic to non-tumorigenic GES-1 cells when compared with GEM and 5-FU [16].

As shown in Figs. 1(a)-(f) [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49] and Table S1, increasing evidence has revealed that quassinoids possess potent cytotoxic properties against a variety of cancer cells, including hepatoma and breast cancer cell lines. While many of these findings are preliminary screening results, a closer look at the anticancer potential of quassinoids is justified. A preliminary structure-activity analysis suggested that most quassinoids with cytotoxic IC50 values below 100 nmol·L−1 share common structural features, including a pentacyclic C-20 skeleton, α,β-unsaturated ketone and enol, 13-methoxycarbonyl, and C13,20-methyleneoxy bridge (Figs. 1(g) and (h) [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49]; Table S2 in Appendix A). Down the road, these characteristic features may provide a useful reference for designing potent analogs for structural optimization.

Aside from their cytotoxic evaluation, quassinoids have been studied in vivo using animal models (Table 1), revealing their remarkable antitumor properties. For example, bruceine D, at a dose of 1.5 mg·kg−1 intraperitoneal (i.p.) injection, exerted an antitumor effect comparable to that of GEM at a dose of 100 mg·kg−1 (i.p.) in orthotopic pancreatic cancer in mice [16]. Our study has revealed a similar level of antitumor activity between bruceine A (0.5 mg·kg−1; tail vein injection) and GEM (25.0 mg·kg−1; tail vein injection) using the pancreatic cancer xenograft model [14].

2.2. Cytotoxic mechanisms

Three major cytotoxic mechanisms have been shown to be associated with the cytotoxic activity of quassinoids; namely, apoptosis, cell cycle arrest, and engagement of the epithelial-to-mesenchymal transition (EMT) program.

2.2.1. Induction of apoptosis

Quassinoid-induced apoptosis is triggered through three signaling pathways: the intrinsic (mitochondrial-mediated) apoptotic pathway, the extrinsic (death receptor-mediated) apoptotic pathway, and the endoplasmic reticulum stress (ERS) response. Many studies have focused on the intrinsic apoptosis pathway (Fig. 2 and Table 2 [12], [14], [16], [21], [26], [29], [31], [33], [37], [38], [39], [43], [46], [47], [48], [58], [59], [60], [61], [62], [63], [64]).

2.2.1.1. Intrinsic apoptotic pathway

The intrinsic pathway—also known as the mitochondrial apoptosis pathway—is accompanied by a decrease in mitochondrial membrane potential (MMP, Δψm), translocation of cytochrome c (Cyto-c) from the mitochondria to the cytosol, and activation of downstream caspases [65]. Bruceine D has been found to induce cancer cell apoptosis by activating the mitochondrion-mediated pathway [16], [21], [37], [38], [43], [48]. Reactive oxygen species (ROS) generation and activation of the mitogen-activated protein kinases (MAPKs) (p38 MAPK), extracellular regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) pathway play a prominent role in bruceine D-elicited apoptosis. JNK signaling in NSCLC H460 and A549 cells, as well as in breast cancer MDA-MB-231 and MCF-7 cells, can be activated by bruceine D [37], [38]. Another report suggested that bruceine D disrupted the direct interaction between inhibitor of β-catenin and T-cell factor (ICAT) and β-catenin, inducing β-catenin degradation, which in turn induced a decrease in hypoxia-inducible factor (HIF)-1α expression and subsequently jeopardized carcinoma cell metabolism [39].

Our study has revealed bruceine A to be a p38α MAPK activator; it strongly inhibited pancreatic cancer cell growth in vitro and in vivo by interacting with residues Leu171, Ala172, Met179, Thr180, and Val183 in the P-loop of p38α MAPK [51]. In addition, bruceine A induced cell mitochondrial apoptosis via 6-phospho-fructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4)/glycogen synthase kinase 3β (GSK3β)-mediated glycolysis in MIA PaCa-2 cells [14].

Brusatol, an inhibitor of the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway, selectively reduced the protein level of Nrf2 through the enhanced ubiquitination and degradation of Nrf2 [12], [59], [66]. It also induced apoptosis in pancreatic cancer PANC-1 and PATU-8988 cells via the JNK/p38 MAPK/nuclear factor-kappa B (NF-κB)/signal transducer and activator of transcription 3 (STAT3)/B-cell lymphoma 2 (Bcl-2) signaling pathway [60]. Notably, brusatol targeted the STAT3-mediated mitochondrial apoptosis pathway in diverse head and neck squamous cell carcinoma. Docking results suggested that the hydroxyl group of brusatol formed a hydrogen bond with the Asn647 of the SH2 domain, favoring its interaction toward STAT3 [61]. Moreover, a recent study revealed that brusatol and its analogs enhanced the efficacy of the treatment of hematologic malignancies by targeting phosphoinositide 3-kinase γ (PI3Kγ) isoform and suppressing the PI3K/protein kinase B (PKB, also known as AKT) signaling pathway [67]. Consequently, brusatol-induced mitochondrial apoptosis may principally be associated with the inhibition of the Nrf2-mediated antioxidant response.

Dehydrobruceine B, a quassinoid that is structurally similar to brusatol, triggered apoptosis in lung cancer (A549 and NCI-H292) and pancreatic cancer (PANC-1 and Capan-2) cells via the mitochondrial pathway [16], [41]. Moreover, neosergeolide [26], bruceantinol [46], 2-dihydroailanthone [62], and ailanthone [29], [47] induced mitochondrial apoptosis of HL-60, MCF-7, U251, Huh7, and SGC-7901 cells. Furthermore, ailanthone enhanced the apoptosis of gastric cancer cells (AGS, SNU719, and SGC-7901) by inducing a repression of base excision repair through an inhibition of the p23/heat shock protein 90 (HSP90)/X-ray repair cross-complementing 1 (XRCC1) pathway [57].

2.2.1.2. Extrinsic apoptotic pathway

The extrinsic pathway is stimulated by specific factors such as tumor necrosis factor-alpha (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) that can activate caspase-8 and subsequent caspase-3 [68]. The apoptogenic impact of bruceine D on breast cancer cells (MCF-7 and MDA-MB-231) was substantiated by the cleavage of procaspase-3/8 and downregulation of the antiapoptotic proteins B cell leukemia-xL (Bcl-xL), X-linked inhibitor of apoptosis (XIAP), and survivin [38]. Eurycomanone—but not eurycomanol—inhibited TNF-α/tumor necrosis factor receptor 1 (TNFR1)/TNF receptor-associated factor 2 (TRAF2)/transforming growth factor beta-activated kinase 1 (TAK1)/I kappa B kinase α (IKKα)/NF-κB/p60/p65 signaling and upstream MAPK signaling in leukemia Jurkat and K562 cells [63]. Compared with eurycomanol, the α,β-unsaturated ketone of eurycomanone played a significant role in NF-κB inhibition [63]. Similarly, eurycomanone inhibited the activation of AKT/NF-κB signaling in human NSCLC A549 and Calu-1 cells [31]. Inactivation of the NF-κB pathway may be crucial in extrinsic apoptosis induction by eurycomanone.

2.2.1.3. ERS response

Tumor cells are often exposed to intrinsic and external factors that alter protein homeostasis, thereby producing ERS [69]. Treatment with eurycomanone resulted in down-regulation of the endoplasmic reticulum protein 28 (ERp28) in human lung cancer A549 cells [64]. ERp28 is the precursor of endoplasmic reticulum protein 29 (ERp29) and ERp29 is a soluble protein of the endoplasmic reticulum (ER) that is involved in secretory protein products. It is overexpressed in several cancers and is thought to contribute to tumor growth and development by supporting epithelial-stromal interactions [70]. Thus, the inhibition of expression of this protein suggests that eurycomanone could also target the ER machinery.

2.2.2. Cell cycle arrest

Most cytotoxic drugs achieve anticancer effects by inducing the apoptosis of tumor cells, and cell-cycle analysis is a key indicator for evaluating anticancer effects [71], [72]. As depicted in Fig. 3 and Table 3 [12], [14], [16], [23], [26], [29], [31], [33], [38], [41], [44], [47], [48], [62], [63], most quassinoids have been found to induce cell cycle arrest at the G0/G1 phase. Of these, neosergeolide time- and dose-dependently increased the percentage of sub-G0/G1 peaks in HL-60 cells [26]. U251 cells treated with 2-dihydroailanthone were arrested in the G0/G1 phase as well [62]. The inhibitory effect of brusatol on PC6 cells was also closely linked to cell cycle arrest at the G0/G1 phase [12]. Eurycomanone and eurycomanol have been reported to exert a sub-G1 phase arrest in the K562 and Jurkat cell cycle in a time- and dose-dependent manner [63]. Treatment with bruceantin led to an accumulation of multiple myeloma cancer stem cells in the G1 phase [44]. Regarding bruceine D, a gradual but significant increase in the sub-G1 breast cancer cell population (MCF-7 and MDA-MB-231) was observed upon treatment in a dose- and time-dependent fashion [38]. Bruceine D also dose-dependently increased the occurrence of the sub-G1 phase of Capan-2 cells [48]. In comparison, bruceine A promoted G1 cell cycle arrest by decreasing cyclin-dependent kinase 4 (CDK4), CDK6, and cyclin D1 expression in MIA PaCa-2 cells, while PFKFB4 overexpression significantly rescued this decrease in expression [14].

There are also reports that describe quassinoid-induced cell cycle arrests at the G1/S, S, and G2/M phases. For example, ailanthone significantly arrested cells at the G1/S phase by upregulating the expression of p21 and downregulating the expression of cyclins D and E and CDKs 2, 4, and 6 in hepatocellular carcinoma Huh7 cells [47]. Dehydrobruceine B induced cell cycle arrest at the S phase in both A549 and NCI-H292 cells [41]. Brusatol elicited S cell cycle arrest in Hep-2 cells [23]. Bruceine D exerted an S phase arrest in PANC-1 and Capan-2 cells in a dose- and time-dependent manner [16]. In brusatol-treated CNE-1 cells, the protein levels of cyclin D1, cyclin B1, cell division control 2 (Cdc2), and cell division cycle 25c (Cdc25c) all decreased, whereas the protein levels of p-Cdc2 increased, leading to G1/S and G2/M arrest [33]. Eurycomanone caused cell cycle arrest at the G2/M phase in A549 cells and at the S phase in Calu-1 cells [31], while SGC-7901 cells exposed to ailanthone exhibited increased cell cycle arrest at the G2/M phase [29].

2.2.3. The EMT program

EMT plays a crucial role in cancer progression, metastasis, and drug resistance. Cells undergoing EMT may display decreased expression level of the epithelial genes (e.g., E-cadherin) and increased expression level of the mesenchymal genes (e.g., N-cadherin and vimentin) [73]. The quassinoid-mediated EMT program was summarized in Fig. 4 and Table 4 [12], [23], [25], [32], [38], [57], [74]. Brusatol has been found to suppress the activation of EMT in liver cancer Bel7404 cells both in vivo and in vitro via a downregulation of the mesenchymal biomarkers (N-cadherin and vimentin), MMP2, and MMP9, together with an upregulation of the epithelial biomarker E-cadherin [32]. Brusatol also exerted appreciable inhibition against the migratory capacity of PC9 cells [12]. It inhibited lipopolysaccharide-induced EMT via deactivation of the PI3K/AKT/NF-κB signaling pathway in human gastric cancer SGC-7901 cells [25] and inhibited cell proliferation and metastasis by abrogating JAK2/STAT3-signaling-mediated EMT in laryngeal cancer Hep-2 cells [23].

Glaucarubinone exhibited anti-migratory and anti-invasion effects in Huh7 cells by suppressing the MMP activities (MMP2 and MMP9) and inhibiting the MAPK/Twist1 pathway [74]. Bruceine D impeded the migration of MCF-7 and MDA-MB-231 cell lines [38]. Ailanthone inhibited the migration and invasion of gastric cancer cell lines, including AGS, SNU719, and SGC-7901 [57].

All in all, the apoptotic properties of quassinoids have been demonstrated in a number of cancer cell lines, although the exact mechanism of action remains to be elucidated in more detail. Future research into chemical modifications is needed to generate molecules that can target specific signaling pathways relevant for cancers.

3. Safety evaluation of quassinoids

In general, quassinoids exert mild cytotoxicity on human normal cells and show no obvious organ toxicities in mice. For example, bruceine D (Table 5 [16], [21], [26], [37], [48]) exerted a mild cytotoxic effect on normal human GES-1 cells with IC50 > 487.33 μmol·L−1, indicating that it is much less toxic than the first-line drugs GEM (0.49 μmol·L−1) and 5-FU (12.76 μmol·L−1) [16]. Bruceine D also exhibited modest cytotoxicity toward non-tumorigenic hepatocyte WRL68 and pancreatic progenitor cells, with IC50 values of 276.56 and 162.48 mmol·L−1, respectively [48], and it did not show apparent toxicity in human umbilical vein EA.hy926 (IC50 164.6 μmol·L−1) and HUVECs (IC50 98.7 μmol·L−1) [21]. Moreover, bruceine D had a much milder cytotoxic effect on normal lung epithelial BEAS-2B cells (48 h, IC50 4.7 μmol·L−1) than on NSCLC cells [37].

Animal data are also available in the literature to suggest a relatively non-toxic effect of some quassinoids. For example, no obvious organ toxicity and no significant differences in blood biochemical markers were observed in tumor-bearing BALB/c nude mice after treatment with brusatol (2.0 mg·kg−1), bruceine D (1.5, 3.0, and 40.0 mg·kg−1), or bruceantin (1.0 and 2.0 mg·kg−1) [16], [18], [21], [23], [24], [32], [33], [50] (Table 6 [14], [16], [18], [21], [23], [24], [32], [33], [47], [50], [51], [57]). Importantly, no signs of distant organ metastasis in mice were observed, based on the results of a bioluminescence test [16]. Ailanthone, at doses of 2-15 mg·kg−1, was reported to exhibit no obvious organ toxicity in BALB/c nude mice [47], [57]. Moreover, bruceine A treatment (either by tail vein injection or intraperitoneal injection at doses as high as 4 mg·kg−1) caused no obvious organ toxicity in tumor-bearing mice [14], [51].

4. Potential benefits of combining quassinoids with clinical anticancer drugs

Resistance has always been a frustrating problem in cancer therapy. In this respect, quassinoids have been found to be able to sensitize resistant cancer cells to chemotherapeutic drugs and ionizing radiation (Table 7 [24], [31], [34], [50], [52], [53], [58], [75], [76], [77], [78], [79]). Research data have shown that constitutively high levels of Nrf2 promote cancer formation and contribute to chemoresistance [80], [81]. Under basal conditions, Nrf2-dependent transcription is repressed by the negative regulator Keap1 [82]. However, when cells are exposed to oxidative stress, electrophiles, or chemopreventive agents, Nrf2 escapes Keap1-mediated repression and activates antioxidant-responsive element-dependent gene expression to maintain cellular redox homeostasis [82]. The Keap1-Nrf2 molecular complex contributes to the regulation of cellular defense mechanisms that enhance survival. Elements of this Keap1-Nrf2 regulatory pathway for cell survival hold strong promise as targets for interventions [83]. Brusatol, a unique Nrf2-inhibitor [60], can sensitize a broad spectrum of cancer cells and xenografts to chemotherapeutic drugs. The combination of brusatol and cisplatin was found to induce apoptosis, reduce cell proliferation, and inhibit tumor growth in lung cancer A549 cells and A549 xenografts more substantially than cisplatin treatment alone [53]. Similarly, brusatol enhanced the cytotoxic efficacy of GEM in both pancreatic cancer cells and PANC-1 xenografts [75]. Moreover, a combination of brusatol and sorafenib led to stronger cytotoxic activity on hepatic OR6 cells by reducing the level of Nrf2 protein [76]. Brusatol also reduced the colorectal cancer burden and improved the efficacy of irinotecan therapy via inhibition of Keap1/Nrf2/Nqo1 signaling [52]. A recent study revealed that brusatol/cytarabine co-therapy elicited a synergistic anti-acute myeloid leukemia effect via Nrf2-mediated glycolysis [24]. All in all, brusatol seems to be able to enhance the efficacy of chemotherapy through inhibition of the Nrf2-mediated defense mechanism.

A common feature of drug resistance and metastasis is profound resistance to apoptosis [84]. This raises the notion that deregulation of the apoptotic pathways may be a key determinant in the development of chemoresistance [85]. Brusatol synergistically enhanced the anticancer effects of cisplatin on colorectal cancer CT-26 cells via the intrinsic and extrinsic apoptotic pathways [77]. It also increased the efficacy of cabergoline against pituitary adenomas via the ROS-mediated inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway [58]. Moreover, treatment with a combination of brusatol and GEM or 5-FU led to interruption of the metastatic characteristics of pancreatic cancer cells (PANC-1 and Capan-2) by regulating the expression of EMT markers (E-cadherin and vimentin) [50]. Similarly, brusatol in combination with paclitaxel inhibited the metastatic potential of triple-negative breast cancer cells [34].

Other quassinoids have also been demonstrated to be active in potentiating the potency of clinical drugs, including within drug-resistance scenarios. For example, dehydrobruceine B enhanced cisplatin-induced cytotoxicity through regulation of the mitochondrial apoptotic pathway in lung cancer A549 cells [78]. Glaucarubinone was shown to be able to sensitize human oral cancer KB cells to paclitaxel by inhibiting the ABC transporters via a ROS-dependent and p53-mediated activation of the apoptotic signaling pathways [79]. Eurycomalactone sensitized NSCLC cells to cisplatin via the intrinsic apoptotic AKT/NF-κB pathway [31]. A recent study revealed that bruceantin targeted HSP90 to overcome resistance to hormone therapy in castration-resistant prostate cancer [18]. In addition, ailanthone targeted co-chaperone protein p23 and prevented the interaction of androgen receptor (AR) with HSP90, thereby overcoming MDV3100 (AR antagonist) resistance in castration-resistant prostate cancer [86].

Intriguingly, a combination treatment with brusatol and ionizing radiation overcame the radio-resistance of lung cancer A549 cells by promoting ROS production and increasing deoxyribonucleic acid (DNA) damage [87]. Redox-sensitive micelles composed of disulfide-linked pluronic-linoleic acid enhanced the cytotoxic efficiency of brusatol in both Bel-7402 and MCF-7 cells [88].

Current evidence has revealed the potential benefits of a combination of quassinoids with clinical anticancer drugs to overcome clinical resistance. Further studies are warranted.

5. Conclusions and future perspectives

Despite advances in biomedical technologies and the invention of new treatment modalities, chemotherapy using cytotoxic compounds remains the mainstream option for cancer therapy today. Nevertheless, the severe side-effects of these chemotherapeutic agents often reduce the clinical efficacy; therefore, there is always a need to search for new drugs with higher efficacy and/or better tolerability.

Natural products have played a key historic role in cancer therapy (e.g., Catharanthus alkaloids and paclitaxel), and the plant metabolite pool remains a viable and rich source of bioactive substances with great potential for development into useful drugs. These substances typically possess advantageous structural features in comparison with many synthetic compounds in terms of drug properties, such as the presence of a larger number of sp3 carbons, more oxygen atoms providing H-bond acceptors and donors, higher hydrophilicity, and greater molecular rigidity. Quassinoids contain such structural properties. Thus, increasing evidence has revealed quassinoids to be potential candidates for anticancer drug development. The literature demonstrates, for example, the anti-proliferative potency and selectivity of brusatol, bruceine A, and bruceine D; moreover, their in vivo efficacies are comparable to those of the clinical anticancer agents camptothecin, GEM, and 5-FU. It is anticipated that—once structural optimization is carried out—the core structure (Fig. 1(h)) of these bioactive compounds can serve as a prototype.

A constitutively high level of Nrf2 has been shown to promote cancer formation and contribute to chemoresistance [80], [81], and deregulation of the apoptotic pathways may be a key determinant in the development of chemoresistance in tumor cells [85]. Evidence is now available to demonstrate the contribution of quassinoids (e.g., brusatol) as adjuvants to current chemotherapy regimens, possibly via Nrf2 inhibition and/or apoptosis regulation. Further studies to clarify the exact mechanism are justified. Moreover, brusatol synergistically enhances the antitumor effects of several clinical anticancer drugs (i.e., cisplatin, paclitaxel, GEM, 5-FU, cabergoline, and cytarabine) via the intrinsic and extrinsic apoptotic pathways. These findings indicate the potential clinical benefits of combining brusatol with clinical anticancer drugs.

To conclude, although the detailed mechanisms of action of quassinoids have not yet been elucidated, this class of natural compounds has clearly demonstrated promising antiproliferative properties that warrant further studies. Moreover, probing into chemical modifications to optimize the pharmacological properties of quassinoids (e.g., brusatol, bruceine A, bruceine D, bruceantin) will likely generate more active and less toxic analogs for drug development. Our group has demonstrated the cytotoxic properties of brusatol, bruceine A, and bruceine D [13], [14], [48], [51], [89], [90], and it is our hope that this overview will inspire further research interest in this group of unique and special plant metabolites.

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (82274085), the Natural Science Foundation of Jiangsu Province (BK20220478), and the Natural Science Foundation of Jiangsu Higher Education institutions of China (22KJB360010).

Compliance with ethics guidelines

Cai Lu, Si-Nan Lu, Di Di, Wei-Wei Tao, Lu Fan, Jin-Ao Duan, Ming Zhao, and Chun-Tao Che declare that they have no conflict of interest or financial conflicts to disclose.

Appendix A. Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.eng.2023.11.022.

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