Anti-cancer effects of aloe-emodin


Aloe-emodin (1,8-dihydroxy-3-hydroxymethyl-anthraquinone), derived from some Chinese edible medicinal herbs, exerts a potential anticancer activity on various cancer cells, making it a drug candidate for cancer therapy.

Supplementing the diet with nutraceuticals containing con-centrated levels of bioactive nutrients, as opposed to obtaining those nutrients solely from food, can be beneficial. Certain anthraquinones, such as aloe-emodin and rhein (Figure 1), are phytochemicals that can be used to restore compromised health [3].

Aloe-emodin is one of many bioactive anthraqui-none components of aloe vera (Aloe barbadensis miller),a perennial cactus-like plant found in tropical climates world¬wide. Aloe has been used as a traditional remedy in many cul¬tures for centuries, and it continues to be extremely popular among both cancer and non-cancer patients [4].

Aloe-emodin possesses numerous beneficial biochemical properties. The compound has been used as an anti-inflammatory agent, an immunomodulator, and mediator of wound healing [5]. The most notable effect is that of an antineoplastic agent.

Figure 1
Chemical structure of aloe-emodin and structurally related anthraquinones addressed in this paper.

In summary, aloe-emodin exhibits an array of anti-tumor effects in various cancer cell lines, including induction of apoptosis, cell cycle arrest, modulation of immune signaling, and cell mobility alterations. Aloe-emodin reduces cancer cell viability through extrinsic (TNF-a and FASL) and intrinsic (cytochrome c/caspase 9) apoptosis pathways, which coincide with deleterious effects on mitochondrial membrane permea-bility and/or oxidative stress via exacerbated ROS production.

The apoptotic pathways are illustrated in (Figure 2) Aloe-e-modin further causes cell cycle arrest through cyclin and cy-clin-dependent kinase downregulation. The cell cycle path¬ways and molecular regulators are depicted in (Figure 3) Al-oe-emodin also decreased transcription factor activity and al¬tered transcriptional expression and/or protein levels of nu-merous cell signaling proteins important in proliferation and metabolism.

In certain cancer cell lines, aloe-emodin induced immune signaling by upregulating, activating, and/or releasing interleukins, GM-CSF, NF-KB, and growth factors. Finally, by altering cell migration, invasion, and adhesion, aloe-emodin negatively affected tumor cell outgrowth propensity.

Figure 2.
Apoptotic pathways and their regulation. Adapted from:
Figure 3.
The cell cycle and its regulating factors. Adapted from:

Pyroptosis, a newly recognized regulated cell death (RCD), is characterized by cell swelling and bubble-like morphology, which is different from apoptosis (Fang et al., 2020). Pyroptosis was initially recognized in immune cells as a general inflammation response against bacterial infection in the field of inflammatory diseases (Bergsbaken et al., 2009).

In this case, gasdermin D (GSDMD) was cleaved by caspase-1/4/5/11, and its produced N-terminal fragment mediates the formation of the pores on the plasma membrane (Shi et al., 2015; Man et al., 2017). Activation of caspase-3 by chemotherapy drug could also induce pyroptosis by gasdermin E (GSDME) cleavage.

The produced N-terminal fragment of GSDME causes pyroptosis by translocating to the plasma membrane (Jiang et al., 2020). Gsdme knock-out caused resistance to chemotherapeutic drugs in specific cancer cells and reduced chemotherapy-induced tissue damage in mice (Wang et al., 2017).

Like chemotherapy drugs, natural products from Chinese medicinal plants possess potent anti-tumor activity, increase chemotherapy sensitivity and reduce its adverse effects, which supplements conventional chemotherapy anti-cancer drugs (Talib et al., 2021). The anti-cancer function of pyroptosis by chemotherapy drugs is rather well reported, but the effects of the active ingredient of the Chinese herbal medicines on pyroptosis are largely unknown.

Aloe-emodin (AE) is one of the anthraquinones compounds derived from traditional Chinese medicinal plants, such as Rheum palmatum L., Aloe vera (L.) Burm. f., and Polygonum cuspidatum Willd. ex Spreng.(Wang et al., 2008; Mandrioli et al., 2011; Wu Z. et al., 2019).

Emerging studies are focusing on the anti-cancer properties of this compound. AE induces cell cycle arrest and triggers cell death in various cancer cells, and also increases the cellular sensitivity to chemotherapeuticagents (Chen et al., 2004; Chihara et al., 2015; Sanders et al., 2018). Caspase activation may also lead to GSDMs-mediated pyroptosis. Still, the effects of Aloe Vera or AE on pyroptosis in cancer cells have not been reported.

Here, we demonstrated that aloe-emodin triggers cell death through GSDME-dependent pyroptosis in HeLa cells. AE treatment induces mitochondrial dysfunction, leading to ROS production, cytosol release of cytochrome c, mitochondrial translocation of Bax and AIF, caspase-9 activation, and GSDME cleavage by active caspase-3.

Furthermore, transcriptomic analyses show the potential cellular pathways upon AE treatment. Thus, our study reveals a novel role of AE in cancer cell pyroptotic death and provides a systematically transcriptional analysis of pathways and cell responses in HeLa cells. Collectively, our data provide a theoretical basis for applying anthraquinone derivatives in the treatment of GSDME-expressing cancers.

Aloe-emodin exhibits a broad spectrum of pharmacological benefits, such as anticancer, anti-inflammatory, antivirus, antibacterial activities (Dong et al., 2020). Of most importance, AE shows remarkable anticancer effects in lung, breast, colon, pancreatic cancer cells by inducing apoptosis and inhibiting cancer cell proliferation (Sanders et al., 2018).

Mechanically, AE affects the MAPKs, PKC, Ras/ERK, ROS-JNK, PI3K/Akt/mTOR pathway (Acevedo-Duncan et al., 2004; Tu et al., 2016; Tseng et al., 2017; Dou et al., 2019; Shen et al., 2020), and regulates the expression of a set of genes, such as the casein kinase II, ALP, c-Myc, ERα, NAT, and NF-κB (Chen et al., 2014; Dong et al., 2020).

To our knowledge, we first discovered that AE could trigger pyroptosis by inducing mitochondrial dysfunction and activating the Bax/caspase9/caspase3/GSDME pathway in HeLa cells (Figure 7). In addition, we provide a systematically transcriptional analysis of pathways and gene expression in AE-treated cells.

A schematic diagram of this work. Aloe-emodin can induce caspase-8 activation, Bid cleavage, BAX translocation to permeabilize the mitochondrial membrane and release cytochrome c into the cytosol. Cytochrome c then activates caspase-9 and subsequent caspase-3. Active caspase-3 mediates the GSDME cleavage, and GSDME-N could directly oligomerize and cause plasma membrane lysis which will cause pyroptosis characteristics, including LDH release and the formation of plasma membrane bubbles.

Both activations of GSDMD and GSDME could induce pyroptotic cell death. However, it seems that GSDME, rather than GSDMD, contributed to AE-induced pyroptosis because SW480 cell, which has a high level of GSDMD but without GSDME expression, was refractory to AE-caused pyroptosis.

On the contrary, in GSDME-expressing cells such as A375 and MCF7 cells, GSDME was cleaved by caspase-3 cleaves, and the pore-forming ability of the N-terminus was released. Therefore, AE may trigger pyroptosis in GSDME high expression cells but apoptosis in GSDME-deficient cells.

Aloe-emodin could induce caspase activation via the death receptor pathway (caspase-8 activation) and the mitochondrial pathway (caspase-9 activation) (Figure 2E). Suppression of caspase-8 inhibited AE-induced the cyto c release and caspase-9 activation (Lin et al., 2010), indicating that the death receptor pathway controlled the AE-induced mitochondrial dysfunction.

In consistent with this, we also observed that AE induced Bid cleavage (Figure 5F). Since activation of caspase-8 in the death receptor pathway results in cleavage of Bid, and translocation of activated Bid activates mitochondria pathway (Yin, 2000; Kim et al., 2017), AE-induced mitochondrial dysfunction is then subsequently linked via cleavage of Bid to the death receptor pathway (Figure 7).

Conventional chemotherapy effectively inhibits tumor growth, but the tumor becomes insensitive to chemotherapy in the later stage, and many patients relapse over time (Norden et al., 2008). Chemotherapy resistance is one of the significant problems for effective clinical therapy. In etoposide-resistant melanoma cells, loss of GSDME decreased cell response to etoposide.

In contrast, over-expression of GSDME increased the cell sensitivity to etoposide, suggesting that increased GSDME activation is related to reduced etoposide resistance (Lage et al., 2001). Interestingly, a combination of AE or the Aloe vera extract increased the cellular sensitivity to chemotherapeuticagents and was more effective in killing cancer cells (Luo et al., 2014).

Still, the mechanism of this action is largely unknown. Our results showed that AE activates the caspase-9/caspase-3/GSDME axis. However, it is worth noting that the ability of AE to induce pyroptosis is much lower than that of DDP, because AE-induced pyroptosis may require a higher concentration or more treatment time (Figure 3D).

In consistent with this, PLK1 inhibitor BI2536 can increase cisplatin chemosensitivity by accelerating GSMDE-mediated pyroptosis, but BI2536 treatment alone only causes GSMDE activation to a much less extent (Wu M. et al., 2019). Thus, these findings may explain potential roles in reversing chemotherapyresistance in GSDME-expressed cancer cells.

Several anthraquinones derivatives are found in the well-known Chinese herbal medicines, and have been developed as pharmacological tools and drugs (Malik and Müller, 2016; Diaz-Munoz et al., 2018). Besides AE, we found that emodin-treatment could also trigger GSDME cleavage. By preliminary comparison of the chemical structures of the six anthraquinones in this study, we found that AE and emodin share similar free hydroxyl groups at positions 1 and 3 (Figure 4), which may be the reason for GSDME cleavage.

However, it needs to be confirmed using more derivatives. Thus, it is intriguing to investigate whether other anthraquinone derivatives also induce pyroptosis and find out which anthraquinones have the most potent effects or whether/how they could interact with each other. Thus, this study reveals a novel pharmacological characteristic of anthraquinone derivatives, which provides valuable information for the potential use of anthraquinone containing Chinese herbs.

We here showed that AE could kill GSDME-expressed cancer cells by pyroptotic cell death, making it a potent anti-cancer agent. In addition, GSDME-mediated pyroptosis of tumour cells enhances the it phagocytosis by tumour-associated macrophages, and triggers the recruitment of immune cells to induce anti-tumor inflammatory responses (Zhang et al., 2020; Li et al., 2021).

However, it should be noted that GSDME is expressed in various normal tissues, including immune system cells ( Thus, AE-mediated pyroptosis may induce toxicity and cause disorder in immune system in certain normal human cells. There have been negative effects reported on AE, such as hepatotoxicity and nephrotoxicity (Zhu et al., 2012; Dong et al., 2017; Dong et al., 2020).

Besides, because AE is difficult to be absorbed by the small intestine and has a short half-life (Yu et al., 2016), it has not been used clinically extensively. Thus, researches are urged to enhance its oral bioavailability, improve tumor-targeting property, and reduce the toxicity to normal cells (Şeker Karatoprak et al., 2022).

One in vitro study reported that AE-loaded in SBA-15 demonstrated better water solubility, and exhibited particular toxicity on HeLa cells and little effect on the normal cervical cells (Jangra et al., 2021), but extensive in vivo researches are required before its clinical implications.

Taken together, here we found that AE induces mitochondrial dysfunction and activates the Bax-caspase9-caspase3-GSDME axis. AE exerts pyroptosis in the GSDME-expressed tumor cells. Besides, AE treatment causes extensive changes in gene expressions and cellular pathways. These results of this study suggest a novel mechanism for anthraquinone derivatives in the treatment of cancer cells.

1. Bladder cancer
In bladder cancer cells (T24), aloe-emodin induced time-and dose-dependent apoptosis [7]. The cell death induction was accompanied by perturbation of mitochondrial membrane potential and reduced levels of cyclin-dependent kinase (CDK) 1, cyclin B1, and BCL-2 after treatment with aloe-emodin.

2. Cervical cancer
Cervical cancer cells (HeLa) were treated with aloe-emodin, which caused cell cycle arrest in the G2/M phase. The cells showed a decrease in cyclin A and CDK2, which reduces the cell’s ability to proliferate, and suppression of protein kinase Ca (PKCa) and c-MYC, signifying that proliferation and dif¬ferentiation were suppressed [8]. Increases in cyclin B1, CDK1, and alkaline phosphatase (ALP) activity were observed along with inhibition of proliferating cell nuclear antigen (PCNA), showing decreased proliferation.

3. Colon cancer
It has been previously shown that 1,8-dihydroxyanthra-quinone (DHA) laxatives are associated with colon cancer development [9]. SW480 carcinoma cells, VACO235 adenoma cells, and normal colonic epithelium were treated with various DHA laxatives to determine their effects. SW480 carcinoma cells showed a dose-dependent increase in urokinase secretion (an enzyme that digests extracellular matrix, which could in¬crease tumor cell migration and metastasis, but also causes cell lysis) that caused a reduction in cell numbers by DHA-agly-cones. Rhein and aloe-emodin (types of DHA laxatives) in¬creased BrdU (5-bromo-2′-desoxyuridine; a marker of cell proliferation) by 37% and 50%, respectively. In contrast, pre-malignant VACO235 adenoma cells did not show an increase in urokinase secretion by sennidine A/B and aloe-emodin. However, cell growth and DNA synthesis increased as reflect-ed by elevated BrdU staining. DHA laxatives had no effect on the normal colorectal epithelium [9]. The anti-proliferative effect of aloe-emodin in WiDr cells (colon cancer cell type) was shown by suppression of phorbol-12-myristyl-13-acetate (PMA), which induces tumor migration and invasion [10]. Aloe-emodin downregulated messenger RNA expression and promoter/ gelatinolytic activity of matrix metalloproteinase (MMP)-2/9 and decreased Ras homologue gene family mem-ber B (RHOB) expression. Nuclear translocation of and DNA binding by NF-KB were suppressed along with vascular endo-thelial growth factor (VEGF), demonstrating that aloe-emodin targets multiple molecules necessary for tumorigenesis. Cell cycle arrest in WiDr cells occurred in the G2/M phase with inhibition of cyclin B1. Another study showed that apoptosis was induced through caspases-6/9, with specific caspase-6 activation by aloe-emodin [11].

4. Gastric cancer
Gastric carcinoma (AGS, NCI-N87) cells treated with aloe-emodin demonstrated mitochondrial release of apoptosis-inducing factor (AIF) and cytochrome c-mediated activation of caspase-3[12]. AGS cells showed greater sensitivity to al-oe-emodin than NCI-N87 cells. Another study showed that MKN45 cell growth was substantially inhibited by both aloe-emodin and emodin, but more so by emodin [13]. These cells were arrested in the G0/G1 and G2/M phase by aloe-emodin and emodin, respectively. Time- and dose-dependent inhibition was demonstrated in MGC-803 cells, with an increase in S phase and a decrease in ALP activity [8]. Another study showed a cytostatic effect in MGC-803 and SGC-7901 cells, with a significant decrease in cell migration [14]. SGC-7901 cells became arrested in the G2/M phase in a time and dose-dependent manner, with a decrease in cell cycle-inducing proteins.

5. Leukemia
Monoblastic leukemia (U937) cells were treated with aloe¬emodin, resulting in reduced proliferation rate. Reactive oxygen species (ROS) and NO production, phagocytosis, and intracel-lular acidity also increased [15], the significance of which is currently elusive.

6. Lung cancer
Researchers in one study on human lung non-small cell car¬cinoma (H460) treated the cells with aloe-emodin and exam¬ined the cells with 2D electrophoresis. They found a time- de¬pendent reduction in ATP, lower ATP synthase expression, and increased mitochondrial damage with unaffected lactate dehy-drogenase (LDH) levels, suggesting the induction of apoptosis. HSP60, HSP70, and protein disulfide isomerase increased, which were hypothesized to cause apoptosis by augmenting endoplasmic reticulum stress [16].

Another series of five different studies by Lee et al. evalu-ated aloe-emodin and emodin in lung squamous carcinoma (CH27) and lung non-small cell carcinoma (H460). The first study demonstrated apoptotic changes through nuclear mor-phological change, DNA fragmentation, increased the relative abundance of cytochrome c levels, activation of caspase-3, and decreased levels of PKC isozymes generally [17]. The second study showed that CH27 cells underwent apoptotic cell death in an irreversible dose- and time-dependent manner, which coin¬cided with DNA fragmentation. BAK, BAX, and cytochrome c were elevated in the cytosol, consistent with the intrinsic apoptosis pathway [18].

In the third study, aloe-emodin treat¬ment was associated with an increased release of nucleophos-min into the cytoplasm, but no change in its gene expression [19]. Nucleophosmin is a nucleolar phosphoprotein that hyp-eraccumulates in the nucleoplasm of malignant cells and de¬creases with drug-induced apoptosis. This study showed that nucleophosmin protein levels were increased, but that the pro¬tein predominantly localized to the cytoplasm in its (inactive) proform.

It was concluded that this could be a possible mecha¬nism in aloe-emodin-induced apoptosis in cancer cells. In the fourth study, aloe-emodin caused single strand DNA breaks and a decrease in the levels of DNA repair enzymes [20]. The final study supported programmed cell death via anoikis and apoptosis of H460 cells through photo-activated aloe-emodin [21]. Anoikis is a form of programmed cell death whereby the cell separates from its environment and eventually dies be¬cause it no longer receives nutrients from its surroundings. In apoptosis, specific cell signals are given to the intact cell to shut down. Increased protein expression of a-actinin and mi-togen-activated protein (MAP) kinase members was observed, and apoptosis was mediated through caspase-dependent intrin¬sic and extrinsic pathways.

In another study, aloe-emodin treatment resulted in time-and dose-dependent irreversible cell death of human lung non-small cell carcinoma (H460) [22]. Aloe-emodin decreased BCL-2, which abrogated the inhibition of pro-apoptotic pro-teins (such as BAK and BAX) and increased gene expression of p38 and caspase-3 activity, exacerbating apoptosis.

7. Liver cancer
Aloe-emodin inhibited cell growth and induced apoptosis in hepatoma (Huh-7) cells in a time- and dose-dependent manner [23]. DNA fragmentation and ROS levels were increased with a reduction in CAPN2 (calpain-2) and UBE3A (ubiquitin pro¬tein ligase E3A). These two proteins are involved in protein degradation via proteasomal processing, which enables maintenance of normal cellular activity. With their decrease, cells are unable to function and undergo apoptosis. Another study showed that aloe-emodin-treated hepatocellular carci¬noma (HepG2) cells underwent apoptosis through a cas-pase-dependent pathway with cleavage and activation of caspases-3/9 and cleavage of PARP [24]. Execution of intrinsic apoptosis was supported by translocation of cytochrome c. Hepatocellular carcinoma (HCCM and Hep3B) cells under¬went apoptosis via caspases-3/9 and PARP. Activation of p38 was unaffected in all three cell lines. Aloe-emodin-induced apoptosis was seen through oxidative stress and sustained c-JUN N-terminal kinase (JNK) activation.

8. Nasopharyngea cancer
Two studies by Lin et al. showed the effects of aloe-emodin in nasopharyngeal carcinoma (NPC) cells. The first study de¬monstrated that aloe-emodin induced apoptosis via caspase-3 activation with DNA fragmentation [25]. Cell cycle arrest in the G2/M phase was associated with increased cyclin B1-CDC2 complex formation. Matrix metalloproteinase-2 was significantly decreased, with an increase in ROS and cytosolic calcium. The second study showed that aloe-emodin signifi¬cantly inhibited cell growth without affecting viability [26]. Cyclin B1 binding to CDK1 was induced, and aloe-emodin triggered cell cycle arrest in the S and G2/M phase.

9. Neuroectodermal cancer
A study demonstrated dose-dependent cytotoxicity of aloe-emodin in neuroblastoma cells (SJ-N-KP wild-type p53 and SK-N-Be(2c) mutant p53 type) [27]. The SK-N-Be(2c) cells lack transcriptional activity of p53-targeted genes, which al-lowed studying the effect of aloe-emodin in terms of apoptosis. Expression of p53 mRNA was increased in both cell lines, but only SJ-N-KP cells showed an increase in p21, BCL-2, BAX, and CD95 mRNA due to loss of p53 function in SK- N-Be(2c) cells. Both cell lines had a time-dependent increase in p53 levels, with induction of p21 and CD95 protein expression in SJ-N-KP cells.

In addressing glial tumors, one group of researchers treated a transformed glia cell line (SVG) and a glioma U-373MG cell line with aloe-emodin, which delayed the number of cells en-tering and exiting the S phase, indicating inhibited S phase progression [28]. Another study showed aloe-emodin-induced apoptosis of U87 malignant glioma cells through disruption of mitochondrial membrane potential, cell cycle arrest in the S phase, and DNA fragmentation in a time-dependent manner with minimal necrosis [29].

10. Oral cancer
A time- and dose-dependent inhibition of cell growth was found in oral cancer (KB) cells treated with aloe-emodin, with cell cycle stalling in the G2/M phase and a decrease in S phase [30]. ALP activity was increased and no DNA fragmentation was observed.

11. Ovarian cancer
HO-8910M ovarian carcinoma cells were evaluated for mi¬gration and invasion [31]. Migration, invasion, and adhesion were significantly inhibited by aloe-emodin, with a corre¬sponding decrease in focal adhesion kinase (FAK; involved in cellular mobility, and in this case, metastasis) protein expres¬sion and mRNA levels. Aloe-emodin use in these cells attested to its anti-metastatic potential.

12. Prostate cancer
Tumor growth suppression was noted in prostate cancer (PC3) cells treated with aloe-emodin. The normal growth of prostate cells is through mTORC2 and its downstream effects. Following treatment with aloe-emodin, mTORC2’s down¬stream enzymes, AKT and PKCa, were inhibited and hence exhibited decreased phosphorylation activity in a dose-depe¬ndent manner [32]. Aloe-emodin did not affect MAPK, p38, or c-JNK or phosphorylation of ERKs. Proliferation of PC3 cells was inhibited as a result of aloe-emodin binding to mTORC2, with inhibition of mTORC2 kinase activity.

13. Skin cancer
Aloe-emodin had a greater cytotoxic effect in non-mela¬noma cancer cells (epidermoid carcinoma (A431) cells and head and neck squamous cell carcinoma (SCC25) cells) than non-cancerous skin cells (pre-malignant keratinocytic HaCaT cells and Hs68 fibroblasts) [33]. This occurred through upreg-ulation of tumor necrosis factor-a (TNF-a), FAS ligand, and the associated death domains for TNF-R1 and FAS. Aloe-e-modin activated caspases-3/7/8/9 and upregulated p53, cyto-chrome c, and BAX. Intracellular ROS increased, while intra-cellular-reduced glutathione (GSH) was depleted and BCL-2 (anti-apoptotic protein) was down-regulated. Further, al-oe-emodin inhibited cytosolic N-acetyltransferase 1 (NAT1) enzyme activity and mRNA expression in A375.S2 malignant melanoma cells in a dose-dependent manner [34]. NAT1, ex-pressed in many human cancer cell lines, is an enzyme that N-acetylates arylamine carcinogens and drugs (initial metabo-lism) in A375.S2 cells as well as other cancer cell lines.

Aloe-emodin also sensitizes skin cancer cells to chemo-therapy. A combination of aloe-emodin and 5-fluorouracil caused an increase in cell death, as did liposomally delivered aloe-emodin. Another study showed that aloe-emodin and emodin potentiated the therapeutic effects of cisplatin, doxo-rubicin, 5-fluorouracil, and tyrosine kinase inhibitor STI 571 in Merkel cell carcinoma, which is known to be resistant to antineoplastic agents [35]. Aloe-emodin had a small advantage over emodin with respect to anti-proliferative effects when combined with these chemotherapeutic drugs at low concen¬trations, while aloin showed no effect.

Radovic et al. found that aloe-emodin caused A375 mela-noma cells to undergo apoptosis accompanied by BCL-2 downregulation and caspase-mediated apoptosis [36]. An in-teresting finding was that aloe-emodin rescued cells from dox-orubicin- or paclitaxel-induced death in a dose-dependent manner, exhibiting a cytoprotective effect. Accordingly, cau-tion is warranted when using aloe-emodin with these chemo-therapy drugs. Finally, aloe-emodin significantly inhibited Merkel cell carcinoma growth with no effect by aloin [37]. Basic fibroblast growth factor (bFGF), transforming growth factor-p1 (TGFp1), nerve growth factor (NGF), and epidermal growth factor (EGF) did not affect proliferation of Merkel cell carcinoma cells.

14. Tongue cancer
Chen and colleagues investigated the effects of aloe-emodin, emodin, and rhein on SCC-4 tongue squamous cell carcinoma in two studies. The first study revealed a decrease in viability in a time- and dose-dependent manner, with the greatest effect induced by emodin, followed by aloe-emodin, then rhein [38]. Migration and invasion of SCC-4 cells was inhibited, with reductions in MMP-2 and NF-KB, signifying decreased cell mobility. In the second study, cytotoxicity and induction of DNA damage were seen in the same order of magnitude per anti-carcinogenic agent [39]. Expression of DNA-PK, BRCA1, and ATM mRNA (all DNA repair enzymes) was significantly inhibited by aloe-emodin, with varying effects by emodin and rhein. Another study showed that aloe-emodin inhibited SCC-4 cell viability in a dose-dependent manner with S phase arrest and changes in nuclear morphology [40]. Levels of ROS, cal¬cium, and caspases-3/8/9 activity increased in a time-de¬pendent manner, accompanied by a reduction in mitochondrial membrane potential.

15. General/other
Aloe-emodin demonstrated p53-independent apoptosis in FaDu (pharyngeal squamous cell carcinoma), Hep3B (hepa¬toma), and MG-63 (osteosarcoma) cells [41]. This resulted in S phase cell cycle arrest. Caspase-8/10-associated RING pro¬tein (CARP) expression was decreased by aloe-emodin. When CARPs were overexpressed, aloe-emodin-induced apoptosis was attenuated. CARPs normally interact with caspase-8/10 by inhibiting their function through ubiquitin-mediated proteoly-sis. With decreased levels of CARPs, apoptosis is increased.

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