The anticancer effects and mechanisms of fucoxanthin combined with other drugs

Abstract

Purpose

Fucoxanthin (Fx) is a characteristic carotenoid present in brown seaweed that has been shown to have various benefits, including anticancer effects. In vitro studies demonstrated these various effects, including the suppression of cell viability, the promotion of apoptosis, and antiangiogenic, antiproliferative, and antimetastatic activity. Interestingly, combinations of Fx with other drugs have better effects than either Fx or other drugs alone. Although the antiproliferative and cancer prevention activities of the combination of Fx and other drugs are still unclear, several effects have been discovered, including the induction of apoptosis, cell cycle arrest at G1/G0, enhanced gap junctional intercellular communication, and the induction of autophagy via various mechanisms, such as decreasing P-gp, activating the CYP3A4 promoter, increasing reactive oxygen species and cellular uptake and suppressing the PI3K/Akt/NFκB pathway. In this review, we address the anticancer effects and mechanisms of the combination of Fx and other drugs in different types of cancer.

Methods

The relevant literature from PubMed and Web of Science databases is reviewed in this article.

Results

Fx combined with other drugs could enhance the effect of both Fx and the other drug or reduce the dose without reducing the effect, which may create more effective and less harmful therapeutic strategies.

Conclusion

Fx combined with other drugs has significant anticancer effects by various mechanisms and could be a potential therapeutic strategy for different types of cancer.

Introduction

Fucoxanthin (Fx) is a characteristic carotenoid present in edible brown seaweed with a distinct structure consisting of an allenic bond, epoxide group, and conjugated carbonyl group in a polyene chain. Studies have demonstrated the distinct benefits of Fx, including antimutagenic (Nishino et al. 2009), antidiabetic (Nishikawa et al. 2012), antiobesity (Maeda et al. 2005), anti-inflammatory (Kim et al. 2010b), neuroprotective (Zhang et al. 2017), and antitumor activity (Martin 2015). The anticancer behavior is especially of interest; such activity has been found in glioblastoma (Liu et al. 2016), colon cancer, bladder cancer, prostate cancer, liver cancer, leukemia, gastric cancer, cervical cancer, melanoma, osteosarcoma, breast cancer, and lung cancer (Martin 2015). Fx suppresses tumor formation through various mechanisms, including inducing autophagy (Hou et al. 2013), inducing apoptosis, arresting the cell cycle at G1/G0, and enhancing gap junctional intercellular communication, and involving different regulatory events in pathways such as the Akt/mTOR, Bcl-2, SAPK/JNK, JAK/STAT, NFκB and MAPK pathways (Martin 2015).

Recently, an increasing number of studies have focused on the combination of Fx and other drugs, including traditional anticancer drugs (e.g., cisplatin and 5-FU), new drugs still under exploration (e.g., TXR antagonists), and nanocarriers. The anticancer effects of Fx combined with other drugs have been evaluated in colon cancer (Eid et al. 2012; Hosokawa et al. 2004; Ravi et al. 2018), liver cancer (Liu et al. 2012, 2013), leukemia (Almeida et al. 2018), breast cancer (Vijay et al. 2018), and cervical cancer (Jin et al. 2018; Ye et al. 2017). However, combinations of Fx with other drugs have different mechanisms than Fx alone, which will be further discussed in the next section.

In animal experiments, oral administration of Fx showed no toxicity and mutagenicity (Beppu et al. 2009a, b; Iio et al. 2011). Though there are no human experiments of Fx yet, animal experiments have exhibited great anticancer effects Fx either alone or combined with other drugs and indicated the great clinical potential of Fx, which will be further discussed too.

In this review, the anticancer effects, possible underlying mechanisms, and the safety and efficacy, of Fx combined with other drugs in different types of cancer, will be discussed.

Anticancer effects of Fx combined with other drugs

Colon cancer (Fig. 1)

Fig. 1.

The anticancer effects of Fx alone and combined with troglitazone, 5-FU, vinblastine, etc. and packing with CS + GL NGs in colon cancer

Colon cancer is the third and second most commonly diagnosed cancer in males and females, respectively (Torre et al. 2015). Epidemiologic studies have demonstrated that higher consumption of fruits and vegetables, which are abundant in carotenoids, has been linked to a lower risk of colon cancer (Mayne 1996; Slattery et al. 2000). In vitro experiments have proven that Fx has anticancer effects in six colorectal cancer cell lines, including Caco-2, WiDr, SW620, HCT116, DLD-1, and Colo205 cells (Takahashi et al. 2015). Hosokawa et al. showed that Fx effectively decreased the viability of Caco-2 cells by suppressing Bcl-2 protein levels and inducing DNA fragmentation via both caspase-dependent and caspase-independent pathways (Hosokawa et al. 2004). Another study demonstrated that Fx could upregulate p21^WAF1/Cip1 to induce cell cycle arrest at G0/G1 phase in WiDr cells (Das et al. 2005).

Troglitazone has been shown to inhibit cell growth and induce apoptosis through the activation of peroxisome proliferator-activated receptor γ (PPARγ) (Brockman et al. 1998; Shimada et al. 2002). Hosokawa et al. (2004) demonstrated that Caco-2 cell viability was not affected by troglitazone at concentrations lower than 10 µM or by 3.8 µM Fx but was dramatically reduced by the combination of 10 µM troglitazone and 3.8 µM Fx. The results indicated the potential of a chemotherapeutic effect of Fx in combination with troglitazone (Hosokawa et al. 2004). However, the underlying mechanisms have not been uncovered.

ATP-binding cassette (ABC) transporters are associated with multidrug resistance (MDR) by preventing the buildup of a toxic concentration of chemotherapeutic drugs in cancer cells, and combinations of cytotoxic drugs with nontoxic ABC transporter inhibitors represent a new approach to overcome drug resistance (Gottesman et al. 2002). Eia et al. found that Fx is effective at reversing MDR; it significantly and synergistically enhanced the cytotoxicity of eight drugs, including doxorubicin, vinblastine, amphotericin-B, paclitaxel, 5-fluorouracil (5-FU), cycloheximide, etoposide, and cisplatin, in Caco-2 cells (Eid et al. 2012). Furthermore, Fx was found to be a substrate of ABC transporters, especially of P-glycoprotein (P-gp), and to significantly decrease P-gp mRNA levels after 48 h of treatment in Caco-2 cells (Eid et al. 2012). These authors concluded that Fx could reverse MDR and enhance the effects of chemotherapeutic drugs by interfering with ABC transporters, which indicated the synergistic effects of Fx in combination with other traditional antitumor drugs (Eid et al. 2012).

A recent study by Ravi et al. (2018) demonstrated that 10 µM Fx loaded in chitosan (CS) + glycolipid (GL) nanogels (NGs) had greater anticancer activity than control treatments in Caco-2 cells. These authors found that cell viability was significantly lower in the GL NG group (50.5%) than in the micellar group (72.5%) over a 48 h exposure (Ravi et al. 2018). Furthermore, cellular Fx uptake showed a positive correlation in the CS + GL NG groups with enhanced caspase-3 activity (Ravi et al. 2018). Enhanced reactive oxygen species (ROS) generation, increased chromatin condensation and DNA fragmentation, Bcl-2 downregulation, Bax upregulation, and increased mitochondrial membrane polarization were all detected in this experimental group (Ravi et al. 2018). This study proved that CS + GL NGs are effective nanocarriers for Fx delivery to induce the apoptosis of Caco-2 cells and suggested the therapeutic potential of Fx with this nanocarrier (Ravi et al. 2018).

Liver cancer (Fig. 2)

Fig. 2.

The anticancer effects of Fx alone and combined with PXR antagonist and cisplatin in liver cancer

Liver cancer is the second leading cause of cancer death in men in the world (Torre et al. 2015). Fx has been shown to significantly induce G1 arrest and the expression of GADD45, a cell cycle-related gene in human hepatocellular carcinoma HepG2 cells, via different patterns of MAPK signaling and the inhibition of cyclin D/CDK4 (Das et al. 2008; Satomi and Nishino 2009; Yoshiko and Hoyoku 2007). In human hepatocellular carcinoma SK-Hep-1 cells, Fx effectively induced G1 arrest and apoptosis by upregulating Cx32 and Cx43, resulting in enhanced gap junctional intercellular communication, which could increase intracellular calcium levels and cause cell cycle arrest and apoptosis (Liu et al. 2009). Pregnane X receptor (PXR) regulates drug clearance in the liver and intestine via the transcriptional regulation of xenobiotic-detoxifying enzymes and transporters, such as cytochrome P450 (CYP) and MDR1 (Dussault and Forman 2002). PXR activation was reported to have antiapoptotic effects in cancer cells (Gollamudi et al. 2008), and PXR antagonists can decrease cell proliferation (Miki et al. 2006). Liu et al. (2012) demonstrated that Fx markedly decreased PXR-mediated activation of the CYP3A4 promoter and rifampin-induced MDR1 expression in HepG2 cells. Furthermore, the interaction between PXR and its coactivator SRC-1 in HepG2 cells was significantly decreased after treatment with Fx for 24 h (Liu et al. 2012). These results illustrated that Fx decreases rifampin-induced CYP3A4 and MDR1 gene expression by attenuating PXR-mediated CYP3A4 promoter activation and the interaction between PXR and its coactivator, suggesting the potential of Fx as an adjuvant to prevent drug resistance in patients receiving chronic therapy with PXR antagonists (Liu et al. 2012).

Cisplatin is a traditional and widely used anticancer drug that enhances DNA repair and inhibits cell apoptosis (Cepeda et al. 2007; Go and Adjei 1999; Zorbas and Keppler 2005). However, its anticancer effect is limited by acquired or intrinsic resistance (Kartalou and Essigmann 2001). Liu et al. (2013) found that pretreatment with Fx followed by cisplatin treatment significantly decreased HepG2 cell proliferation compared to cisplatin treatment alone. Furthermore, this study demonstrated that Fx could improve the chemotherapeutic efficacy of cisplatin in HepG2 cells via two pathways: one, suppressing cisplatin-induced NFκB expression and increasing the NFκB-related Bax/Bcl-2 mRNA ratio; and two, attenuating the cisplatin-induced mRNA expression of excision repair cross complementation 1 (ERCC1) and thymidine phosphorylase (TP) regulated by ERK, p38, and PI3K/Akt. Thus, these data suggested the therapeutic potential of the combination of Fx and cisplatin in human hepatocellular cancer to decrease cisplatin-induced drug resistance (Liu et al. 2013).

Leukemia (Fig. 3)

Fig. 3.

The anticancer effects of Fx alone and combined with imatinib and doxorubicin in leukemia

Leukemia refers to a group of cancers that usually begin in the bone marrow and result in high numbers of abnormal white blood cells. In adult T-cell leukemia (ATL), Fx induced G1 cell cycle arrest by decreasing the expression of cyclin D1, cyclin D2, CDK4, and CDK6 and inducing the expression of GADD45α (Ishikawa et al. 2008). Fx also induced ALT cell apoptosis by decreasing the expression of Bcl-2, XIAP, cIAP2, and other molecules in the survival and caspase-dependent pathways (Ishikawa et al. 2008). Moreover, Fx inhibited the activation of NFκB and activator protein-1 by suppressing IκBα phosphorylation and JunD expression (Ishikawa et al. 2008). In the human promyelocytic leukemia cell line HL-60, Fx was found to induce apoptosis by reducing the mitochondrial membrane potential and the cleavage of procaspase-3 and poly (ADP-ribose) polymerase without any effect on the protein levels of Bcl-2, Bcl-xL, or Bax (Kotake-Nara et al. 2005). However, others showed that Fx induced apoptosis via ROS mediated by the Bcl-xL pathway (Kim et al. 2010a).

Chronic myelogenous leukemia (CML) accounts for 15–20% of adult leukemia cases (Gu et al. 2012; Yin et al. 2004). As a BCR-ABL tyrosine kinase inhibitor, imatinib mesylate is the first-line therapy for most CML patients. It exerts a pronounced effect on CML by interacting with BCR-ABL ATP-binding sites and consequently inhibiting the phosphorylation of proteins linked to BCR-ABL signaling pathways (Gibson et al. 2013; Mahon et al. 2000). Doxorubicin, a type of anthracycline, is an clinical anticancer agent that inhibits DNA and RNA synthesis, inhibits topoisomerase II to create DNA double-strand breaks, and leads to free radical synthesis (Laroche-Clary et al. 2000; Lebrecht et al. 2004; Park et al. 2005; Thorn et al. 2011). Almeida et al. (2018) investigated the effect of Fx combined with imatinib and doxorubicin on two different CML cell lines, K562 and TK6. Coincubation with 10 µM Fx and the two anticancer drugs caused a 30% increase in cytotoxicity in K562 cells and 56% and 51% inhibition of K562 and TK6 cell proliferation, respectively (Almeida et al. 2018). However, DNA damage did not significantly increase, and apoptosis was not detected, which means that the induction of apoptosis does not seem to be the main mechanism of the antiproliferative effect (Almeida et al. 2018). Although Fx combined with either imatinib or doxorubicin showed therapeutic potential in CML, the underlying mechanisms still need to be further studied.

Breast cancer (Fig. 4)

Fig. 4.

The anticancer effects of Fx alone and combined with doxorubicin in breast cancer

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females worldwide (Torre et al. 2015). Fx and its metabolite fucoxanthinol (Fxol) increased the apoptosis of the estrogen-sensitive cell line MCF-7 and the estrogen-resistant cell line MDA-MB-231 (Rwigemera et al. 2014). Fxol was found to inhibit p65, p50, RelB, and p52 in the NFκB pathway in MDA-MB-231 cells. SOX9 expression was highly correlated with cancer cell proliferation (Rwigemera et al. 2014). The decrease in nuclear SOX9 regulated by NFκB was also found in MDA-MB-231 cells upon treatment with both Fx and Fxol (Matheu et al. 2012; Saegusa et al. 2012; Sun et al. 2013).

Vijay et al. (2018) evaluated the cytotoxicity of four carotenoids, including Fx, β-carotene, lutein, and astaxanthin, in the presence and absence of the minimal cytotoxic dose of doxorubicin in both MCF-7 and MDA-MB-231 cells and discovered that these combinations of carotenoids and doxorubicin significantly reduced cell viability compared to carotenoid or doxorubicin alone at the same concentration. β-Carotene and lutein were used for further mechanistic studies, which revealed that cotreatment with these two carotenoids and low-dose doxorubicin could increase lipid peroxides and ROS levels (Vijay et al. 2018). Furthermore, mitochondrial dysfunction; G1 arrest; caspase signaling; increases in p53, p21, p27, and Bax; and decreases in Bcl-2 and cyclin D1 were detected (Vijay et al. 2018). Meanwhile, the combination of carotenoids and doxorubicin did not show marked cytotoxicity in normal breast epithelial cells (Vijay et al. 2018). These results demonstrated that doxorubicin combined with carotenoids could obviously enhance oxidative stress-mediated apoptosis in breast cancer compared with either carotenoid or doxorubicin alone, and the synergistic effect of this combination could be a new therapeutic strategy for breast cancer (Vijay et al. 2018). Although the mechanisms of the Fx and doxorubicin combination were not elucidated in this previous study, the similar results for β-carotene or lutein combined with doxorubicin suggest that Fx combined with doxorubicin might function via a similar mechanism because Fx is also a member of the carotenoid family. The combination of Fx and doxorubicin was clearly cytotoxic to breast cancer cell lines in the experiments. Therefore, the therapeutic potential of Fx combined with doxorubicin in breast cancer should not be ignored.

Cervical cancer (Fig. 5)

Fig. 5.

The anticancer effects of Fx alone and combined with TRAIL in cervical cancer

Cervical cancer is the second most commonly diagnosed cancer and the third leading cause of cancer death among females in less developed countries (Torre et al. 2015). Hou et al. (2013) discovered that Fx could induce G1 arrest and autophagy. The inhibition of phosphorylated Akt and its downstream target, mTOR, was demonstrated to contribute to the initiation of autophagy (Aoki et al. 2007). Fx was found to attenuate the phosphorylation of Akt and its downstream proteins p53, p70S6K, and mTOR and to enhance the expression of PTEN (Hou et al. 2013). These results demonstrated that Fx induces autophagy-dependent cytotoxicity in HeLa cells through inhibition of the Akt/mTOR signaling pathway (Hou et al. 2013).

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor (TNF) family, can selectively induce cancer cell death (Lemke et al. 2014). However, some cancers gradually become resistant to TRAIL, which limits its anticancer application (Trivedi and Mishra 2015; Wang et al. 2014). Ye et al. (2017) demonstrated that the TRAIL-resistant CaSki subline showed an increase in the PI3K/Akt pathway and was more sensitive to TRAIL combined with either Fx or an Akt inhibitor than to Fx or TRAIL alone, suggesting that the combination of TRAIL with Fx could sensitize TRAIL-resistant cervical cancer cells by inhibiting the PI3K/Akt pathway. Consistent with the above study, Jin et al. (2018) found that PI3K/Akt/NFκB pathway activation was enhanced by TRAIL alone but significantly suppressed by Fx in SiHa cells. Moreover, PI3K and NFκB inhibitors significantly downregulated apoptosis induced by Fx, TRAIL or Fx plus TRAIL (Jin et al. 2018). These two studies jointly demonstrated that the combination of Fx and TRAIL could enhance the apoptosis of cervical cancer cells, especially of TRAIL-resistant cervical cancer cells, via the PI3K/Akt/NFκB pathway and suggested the therapeutic potential of this combination (Jin et al. 2018; Ye et al. 2017).

Studies in vivo

Single and repeated oral dose toxicity study of Fx has conducted in mice (Beppu et al. 2009b). Both single dose study (1000 and 2000 mg/kg) and repeated dose study for 30 days (500 and 1000 mg/kg daily) exhibited no mortality and no abnormalities in gross appearance (Beppu et al. 2009b). Mutagenicity of orally administered Fx (500, 1000 and 2000 mg/kg) was also conducted in mice and the mutagenicity was negative at all doses (Beppu et al. 2009a). Another study conducted single oral and 13-week toxicity studies of Fx in rats which exhibited no mortality and abnormalities in fucoxanthin-administered groups either (Iio et al. 2011). As a result, Fx was proved to have no toxicity to bodies.

An in vivo experiment was conducted on mice using Fxol (the metabolite of Fx) (Terasaki et al. 2017) to test its effects on colon cancer. The suspension of single cells that were dissociated from sphere-forming colorectal cancer cells was injected onto the backbone of NOD-SCID mice (Terasaki et al. 2017). After 2 weeks, there was little difference in body weight between the Fxol and control groups (Terasaki et al. 2017); however, the tumors in the Fxol group were smaller after 8 days of treatment and was significantly smaller after 10 days of treatment than those in the control group (Terasaki et al. 2017). To test the effects of Fxol on leukemia, SCID mice were inoculated with HUT-102 and administered Fxol (Ishikawa et al. 2008). During the 4-week treatment, both the Fxol and control groups showed no adverse effects in general appearance, body weight, and food intake. The tumors in the Fxol group were significantly smaller after 14 days of treatment and weighed significantly less when excised than those in the control group (Ishikawa et al. 2008). The level of the surrogate marker (sIL-2Rα) in serum was significantly lower, and TUNEL assays showed more apoptotic cells of the tumor, in the Fxol group (Ishikawa et al. 2008) than in the control group. To test its effect on cervical cancer, Fx alone, TRAIL alone, and Fx plus TRAIL were administered to nude mice, which had been injected CaSKi cells into posterior flanks (Ye et al. 2017). Although both TRAIL alone and Fx alone groups suppressed tumor growth, the comparison of the volume of the tumors in the Fx plus TRAIL group with that in the TRAIL alone, Fx alone, and control groups demonstrated that the combination of Fx and TRAIL exhibited stronger anticancer effects (Ye et al. 2017). Other experiments in vivo of Fx or Fxol conducted in lymphoma (Yamamoto et al. 2011), melanoma (Kim et al. 2013), lung cancer (Mei et al. 2017), glioblastoma (Liu et al. 2016), and sarcoma (Wang et al. 2012), exhibit similar results. These animal experiments indicated the anticancer efficacy of Fx or Fxol alone or combined with other drugs and its great clinical potential.

Conclusion

A previous review discussed the anticancer effect of Fx and Fxol in different types of cancer and mentioned that combination treatments of Fx and Fxol with anticancer drugs may lead to important new therapeutic strategies with limited risk of MDR in many types of cancer (Martin 2015). In this review, we mainly focused on the effect of Fx in combination with other drugs in both drug-resistant and nondrug-resistant cancers. As summarized in Table 1, the anticancer effects and mechanisms of Fx combined with other drugs are diverse. Although Fx alone has a significant anticancer effect, combinations with other drugs could enhance the effect of both Fx and the other drug or reduce the dose without reducing the effect (e.g., as mentioned above for troglitazone and doxorubicin), which may create more effective and less harmful therapeutic strategies. And Fx has showed no toxicity and great anticancer efficacy in animal experiments, there is great clinical potential of Fx to become a novel adjuvant drug in cancer therapy.

Table 1.

Anticancer effects of Fx combined with various drugs in different types of cancer

Cancer type	Combination drugs	Effects of Fx	Mechanisms
Colon cancer	Troglitazone	Enhancing the reduction in cell viability	Unknown
	5-FU, vinblastine, etc.	Reversing multidrug resistance	Interfering with ATP-binding cassette transporters to decrease P-gp mRNA levels
	Packing with CS + GL NGs	Inducing apoptosis	Increasing the drug concentration in cells
Liver cancer	PXR antagonists	Attenuating CYP3A4 and MDR1 gene expression	Attenuating PXR-mediated CYP3A4 promoter activation and the interaction between PXR and a coactivator
	Cisplatin	Decreasing cisplatin-induced drug resistance	Inhibiting NFκB expression and attenuating DNA repair systems
Leukemia	Imatinib and doxorubicin	Enhancing the antiproliferative effect	Unknown but might not be through inducing apoptosis
Breast cancer	Doxorubicin	Enhancing G1 arrest and apoptosis	Increasing lipid peroxides and ROS levels to enhance oxidative stress-mediated apoptosis
Cervical cancer	TRAIL	Reversing TRAIL resistance	Suppressing the PI3K/Akt/NFκB pathway

The discovered mechanisms are also present

This is the first review focusing on the effects of Fx in combination with other drugs, which broadens the application of Fx as an anticancer drug and provides guiding significance for future studies.

This review has limitations. There have been few studies on Fx combined with other drugs, and these studies have been conducted in only five types of cancer. However, the studies mentioned above reveal significant effects of Fx in combination with other drugs, which could attract more attention to this combination and its potential for application in other types of cancer. In addition, it seems difficult to obtain consensus on the anticancer mechanisms of Fx combined with other drugs from the results of previous studies. This might be because the structure of Fx is complex, and structure–activity relationship studies have revealed various potential targeting molecules. This hypothesis can also explain the various health benefits of Fx, such as the anti-inflammatory and antiobesity activity, as mentioned in the introduction. Moreover, most of these experiments were performed in vitro, and more animal experiments should be conducted to explore the anticancer effect of Fx in vivo. Studies have shown that most dietary Fx may be converted to Fxol in rats (Sangeetha et al. 2010; Sugawara et al. 2002), indicating that the anticancer effects of Fxol combined with other drugs should also be considered.

Taken together, these current findings suggest that Fx combined with other drugs has significant anticancer effects by various mechanisms and could be a potential therapeutic strategy for different types of cancer.

Abbreviations

Fx

Fucoxanthin

Akt

Protein kinase B

mTOR

Mammalian target of rapamycin

Bcl-2

B-cell lymphoma 2

SAPK/JNK

c-Jun N-terminal kinases

JAK

Janus kinases

STAT

Signal transducer and activator of transcription protein family

NFκB

Nuclear factor kappa-light-chain-enhancer of activated B cells

MAPK

Mitogen-activated protein kinase

5-FU

5-Fluorouracil

PXR

Pregnane X receptor

WAF/Cip1

Cyclin-dependent kinase inhibitor 1

PPARγ

Peroxisome proliferator-activated receptor γ

ABC transporters

ATP-binding cassette transporters

MDR

Multidrug resistance protein

P-gp

P-glycoprotein

CS

Chitosan

GL

Glycolipid

NGs

Nanogels

ROS

Reactive oxygen species

Bax

Bcl-2-associated X protein

GADD45

Growth arrest and DNA-damage-inducible protein

CDK

Cyclin-dependent kinase

Cx

Connexin

CYP3A4

Cytochrome P450 3A4

SRC-1

Steroid receptor coactivator-1

ERCC1

Excision repair cross complementation 1

TP

Thymidine phosphorylase

ERK

Extracellular signal-regulated kinase

PI3K

Phosphoinositide 3-kinase

ALT

Adult T-cell leukemia

XIAP

X-linked inhibitor of apoptosis protein

cIAP2

Cellular inhibitor of apoptosis protein 2

IκBα

Nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitorα

Bcl-xL

B-cell lymphoma-extra large

CML

Chronic myelogenous leukemia

BCR

Breakpoint cluster region protein

ABL

Abelson murine leukemia viral oncogene homolog

Fxol

Fucoxanthinol

PTEN

Phosphatase and tensin homolog

TRAIL

Tumor necrosis factor-related apoptosis-inducing ligand

TNF

Tumor necrosis factor

Funding

This study was funded by National Natural Science Foundation of Wuhan (Grant no. WX18Q21 to YC).

Compliance with ethical standards

Conflict of interest

Authors declare that he/she have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.