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Hsia, S. Isoliquiritigenin in Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/7050 (accessed on 17 November 2024).
Hsia S. Isoliquiritigenin in Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/7050. Accessed November 17, 2024.
Hsia, Shih-Min. "Isoliquiritigenin in Cancer" Encyclopedia, https://encyclopedia.pub/entry/7050 (accessed November 17, 2024).
Hsia, S. (2021, February 04). Isoliquiritigenin in Cancer. In Encyclopedia. https://encyclopedia.pub/entry/7050
Hsia, Shih-Min. "Isoliquiritigenin in Cancer." Encyclopedia. Web. 04 February, 2021.
Isoliquiritigenin in Cancer
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cancers13010115

Isoliquiritigenin (ISL), a natural bioactive compound with a chalcone structure, demonstrates high antitumor efficacy. 

isoliquiritigenin cancer

1. Indroduction

ISL is a flavonoid with a simple chalcone structure. The structure of ISL and its metabolites are shown in Figure 1. The previous studies demonstrated the six metabolites detected in phase I[1][2][3], including liquritigenin (M1), 2′,4,4′,5′-tetrahydroxychalcone (M2), sulfuretin (M3), butein (M4), davidigenin (M5), and cis-6,4′-dihydroxyaurone (M6). Among the six metabolites, butein is the more active metabolite in the liver and in HT22 cells, with significant distribution on M1, M3, and M4 (Figure 1) [1][2][4]. Moreover, the previous study reported that the dominant metabolites of ISL are THC (2,4,2′,4′-tetrahydroxychalcone) and naringenin chalcone in lung cells [5] In vivo absorption of ISL occurs in the intestines, transported to the liver for phase II biotransformation[2]. In phase II metabolism, liquiritigenin, glucuronidated ISL, glucuronidated liquiritigenin, and glucuronidated ISL are produced. Only glucuronidated liquiritigenin is predominant[6]. Many studies have suggested that secondary metabolites are involved in different biological activities and pharmaceuticals[1][2][6][7]. Therefore, these metabolites may differ in various cell lines or organs; however, they all share a similar structure to that of chalcone, which contains two aromatic rings connected by an unsaturated carbon chain, resulting in interconnected biological activities.

Cancers 13 00115 g001 550

Figure 1. Metabolites of isoliquiritigenin (ISL). Phase I ISL metabolites were identified to be liquiritigenin (M1), 2′,4,4′,5′-tetrahydroxychalcone (M2), sulfuretin (M3), butein (M4), davidigenin (M5), and cis-6,4′-dihydroxyaurone (M6). Phase II metabolites were glucuronide conjugated process. Note: Figure was modified from[1][2].

2. ISL Pharmacokinetics

Evaluation of the safety of ISL is necessary for future clinical applications. Therefore, many studies, through different routes of administrations, including intravenously (IV), via hypodermic (IH) or intraperitoneal (IP) injection, and orally, have indicated that ISL exhibits a robust absorption capacity (absorption rate: ~60–90 min; oral absorption: >90%) with a strong elimination ability (t1/2: 2–4.9 h)[6][8][9][10]. Moreover, the data showed similar trends among different analytic methods, including high-performance liquid chromatography (HPLC), HPLC–MS/MS, and fluorescence spectrometry (SFS)[6][8][9]. This means that the absorption of ISL is quickly and widely distributed throughout the body[6][8][9][10]. Concentrations of ISL may vary in different tissues, including the heart, liver, lungs, spleen, kidneys, brain, muscles, and fat. ISL distribution mainly relies on the blood circulation, with the brain showing the lowest level of ISL due to the blood–brain barrier (BBB). These results imply that ISL is able to penetrate the BBB and exhibits neuroprotective activity in a male middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia rat model and high fat diet (HFD)-induced ICR mice model[11][12]. Interestingly, only after oral administration does [ISL]plasma exhibit a double-peak of ISL[10][13][14][15], the possible mechanism for which has been proposed as enterohepatic recycling. As a matter of fact, oral administration has become the most advanced application route.

3. ISL Nanoformulations and ISL Derivatives: Improved Efficacy

Generally speaking, poor bioavailability, rapid degradation, fast metabolism, and systemic elimination are the essential factors that lead to insufficient bioavailability. Insufficient bioavailability of ISL means that its efficacy is far less than 20%[6] [10]. The term insufficient bioavailability implies that patients show intolerance to bulk administration of ISL to reach the desired effect, thereby highlighting the need to improve its effectiveness. To improve solubility, enhancing its bioavailability and distribution, encapsulated ISL nanoparticles or nano-ISL have been developed. Below, we summarize various ISL nanoparticles applied in preclinical studies, for example, polymer nanoparticles, liposomes, micelles, solid lipid nanoparticles (SLNs), and polymer conjugates.

  • Nanosuspension: ISL is milled with HPC (hydroxypropyl cellulose) SSL and PVP (polyvinylpyrrolidone) K30 to form a lamelliform or ellipse shape of the nanosuspension. HPC SSL and PVP K30 act as stabilizer. These two nanosuspension particles (size: 238.1 ± 4.9 nm with SSL; 354.1 ± 9.1 nm with K30) do not only improve the solubility issue, but also enhance the cytotoxicity a 7.5–10-fold[16].

  • Nanoencapsulation: Mesoporous silica nanoparticles (MSNs) are a solid material, acting as a biodegradable nanoscale drug carrier. When MSNs are encapsulated with ISL, they improve the efficacy of ISL in vitro and in vivo[17].

  • Lipid–polymer hybrid nanoparticle system:

    3.1.
    iRGD hybrid NPs: The composition of lipid–polymer hybrid nanoparticles (NPs) include lactic-co-glycolic acid (PLGA), lecithin, and a hydrophilic poly-ethylene-glycol (PEG). ISL-loaded hybrid NPs are composed of an inner PLGA core with an outer lipid layer (PEG, lecithin, and iRGD peptides). iRGD peptides (CRGDK/RGPD/EC, a tumor-homing peptides), can deliver drugs to a tumor. In vitro, ISL–iRGD NPs show stronger inhibition effects and induce apoptosis effects. In vivo, ISL–iRGD NPs show stronger effects in the viability of tumor cells. Herein, iRGD-modified lipid–polymer NPs showed better solubility, bioavailability, and targeting distribution[18].
    3.2.
    Hydrophilic polyanion solid lipid nanoparticles (SLNs): SLNs are composed of natural lipids such as lecithin or triglycerides that remain solid at 37 °C. SLNs can protect labile compounds from chemical degradation and can improve bioavailability. Low-molecular-weight heparins (LMWHs) are fragments of heparin showing hydrophilic polyanions that can improve the efficacy of ISL[19].

  • Microemulsion: The self-microemulsifying drug delivery system (SEMDDS) was designed for improving the solubility, absorption, and bioavailability of lipophilic drugs. The SMEDDS comprises ethyl oleate (EO; oil phase), Tween 80 (surfactant), and PEG 400 (co-surfactant). ISL-loaded SMEDDS has been proven to improve the solubility and oral in vivo availability[13].

  • ISL-loaded nanostructured lipid carriers (ISL-NLCs): NLCs mix solid lipids with spatially incompatible liquid lipids, which leads to a special nanostructure with improved properties for drug loading. ISL-loaded NLCs are constructed by glycerol monostearate (MS) and Mi-glyol-812 as the solid and liquid lipid materials to carry the ISL[20]. In pharmacokinetic studies, less than 10% of the NLCs remains in the stomach after oral administration, mainly absorbed in the colon[19]. Moreover, the antitumor effect of ISL-loaded NLCs has been evaluated in sarcoma 180 (S180)-bearing and murine hepatoma (H22)-bearing mice models via IP administration[20]. A biodistribution study showed that the ISL concentration of ISL-loaded NLCs in the tumor is higher 2.5-fold than free ISL. In a skin permeability study, the previous study suggested NLCs as a promising carrier to deliver the ISL[21].

  • TPGS-modified proliposomes: D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) has been selected as an excipient for ISL-loaded TPGS-modified proliposomes (ISL-TPGS-PLP), prepared using the film dispersion method with ISL-loaded proliposomes (ISL–PLP). ISL-TPGS-PLP can enhance the solubility, bioavailability and liver-targeting ability of ISL[14].

  • Polymeric micelles: PEO (polyethylene oxide)–PPO (polypropylene oxide)–PEO (polyethylene oxide) triblock copolymers are highly biocompatible and act as surface-active agents. P123 (PEO20–PPO65–PEO20) can remarkably enhance the retention of poorly soluble drugs in the blood circulation. Another important derivative of Pluronic, F127 (PEO100–PPO69–PEO100), possesses high biocompatibility. Therefore, mixed F127/P123 polymeric micelles have been developed, which have remarkably enhanced bioavailability with high encapsulation efficiency and low particle size. ISL-loaded F127/P123 polymeric micelles (ISL-FPM) improve the solubility as well as enhance the bioavailability and antioxidant activity of ISL [22].

  • Nanoliposomes (NLs): Drug-loaded PEGylated nanomaterials have shown effective cancer cell-killing ability, PEG2000-DPSE-QUE-NLs (polyethyleneglycol-2000-distearoyl phosphatidyl ethanolamine loaded with querce-tin (QUE)) can efficiently disperse in aqueous media compared to controls, and PEGylated (PEG2000-DPSE) NLs have been found to be effective drug delivery vehicles when simply loaded with ISL. ISL-NLs as tumor-targeted drug carriers are more effective in regulating glycolysis in colon cancer cell lines (CRC: HCT116)[23].

  • Hydrogel: Hydrogels are composed of hyaluronic acid (HA) and hydroxyethyl cellulose (HEC), and they can improve the skin permeation of ISL[24].

As described above, many experiments have been conducted to evaluate the various properties of ISL nanoformulation have been developed to address the problems of bioavailability and solubility. Nanoformulation studies have been conducted in vitro and in vivo (Table 1), demonstrating that ISL nanoformulations improve the bioavailability by 2–10-fold[13][20][22].

Table 1. Nano-formulation of ISL.

Formulation Material Particle Size
(nm)		 Model Conclusion Ref
Nanosuspension Hydroxypropyl cellulose-SSL
Polyvinylpyrroli-done-K30		 238.1 ± 4.9
354.1 ± 9.1		 In vitro: A549 HPC SSL‑ISL‑NS and PVP K30-ISL‑NS both improve the solubility and cytotoxic activity of ISL (IC50: ~0.08 µM). [16]
Nanoencapsulation Mesoporous silica nanoparticles ~200 In vitro: mouse primary bone marrow-derived macrophages (BMMs)
In vivo: lipopolysaccharide (LPS)-mediated calvarial bone erosion model (received 50 mg/kg MSNs-ISL; once every 2 days via subcutaneous injection)
Experiment period: 7 days		 MSNs-ISL as an effective natural product-based bone-bioresponsive nanoencapsulation system prevents osteoclast-mediated bone loss (In vitro effective dose: 16~64 µg/mL). [17]
Lipid–polymer hybrid ISL-iRGD nanoparticles ~130
138.97 ± 2.44		 In vitro: MCF-7, MDA-MB231, 4T1
In vivo: 4T1-bearing nude mouse (received 35 µg/kg once every 2 days via IV injection)
Experiment period: 20 days		 RGD modified lipid–polymer hybrid NPs improve ISL in anti-breast cancer efficacy (Effective dose: >12 µM). [18]
LMWH-ISL-SLN 217.53 ± 4.86 In vitro: HepG2
In vivo: Kunming mice (6 female and 6 male; 50 mg/kg via IV injection daily) Experiment period: 14 days		 Pharmacokinetics of LMWH-ISL-SLN demonstrated its safety and better bio-distribution after intravenous administration (In vitro IC50: ~7.45 µg/mL). [19]
Micro-emulsion Self-microemulsifying drug delivery system (SEMDDS) 44.78 ± 0.35 In vivo: SD rat
(oral administration:
a single dose: 200 mg/kg)
Experiment period: 24 h		 ISL-SMEDDS can enhance the
solubility and oral bioavailability of ISL.		 [13]
20.63 ± 1.95 In vivo: SD rat
(oral administration:
twice a day; 20 mg/kg)
Experiment period: 63 days		 [25]
Nanostructured lipid carrier (ISL-NLC) Monostearate and lecithin 160.73 ± 6.08 In vivo: Kunming mice bearing H22 and S180 tumor (intraperitoneal injection daily) Experiment period: 12 days ISL-NLC nanoparticles with high envelopment efficiency with initial burst release, exhibiting superior in vivo antitumor effect and biodistribution. [20]
MS and Miglyol 812 160.73 ± 6.08 In vivo: SD rat
(oral administration:
a single dose: 20 mg/kg)
Experiment period: 36 h		 NLC are valuable as an oral delivery carrier to enhance the absorption of a poorly water-soluble drug, ISL. [15]
Ceramide, cholesterol, caprylic/capric triglyceride 150.2–251.7 In vitro: Franz diffusion cell
In vivo: ICR mice		 NCL improved the skin permeation of
ISL (permeability: 8.48~10.12 μg/cm3).		 [21]
TPGS-modified proliposomes D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS),
proliposomes		 23.8 ± 0.9 In vivo: Swiss-ICR mice
oral administration
Experiment period: 24 h		 ISL-TPGS-PLP had small particle size, high encapsulation efficiency and drug loading capacity, and possessed good storage stability. [14]
Polymeric micelles ISL-loaded F127/P123 polymeric micelles (ISL-FPM) 20.12 ± 0.72 In vivo: SD rat,
(oral administration:
a single dose 200 mg/kg) Experiment period: 24 h		 ISL-FPM act as a promising approach to improve solubility as well as enhance bioavailability and antioxidant activity of ISL. [22]
Liposome Phospholipid and cholesterol 233.1 In vitro: HeLa and SiHa ISL liposome can significantly inhibit the proliferation of human cervical cancer cells in vitro. [26]
Nanoliposome Sodium cholate, cholesterol and IPM were melted with a ratio of 5:1:4 (w/w/w) 82.3 ± 35.6  In vitro: HCT116 and HT29 ISL involved in the glucose metabolism in colon cancer. [23]
Hydrogel systems HA-HEC hydrogels N.A. In vitro: skin permeation study Franz diffusion cells HA-HEC hydrogel showing the stable viscoelastic be haviour and the optimal adhesiveness has potential to enhance skin permeation of IS (permeability: 20 μg/cm3). [24]
ISL-derived new compounds offer another solution to improve the bioavailability and water-soluble issues[27][28][29][30][31][32] . Considering the chalone structure, the α,β-unsaturated ketone is an important part of its biological activity by modifying on the phenol ring to improve the performance of ISL. We summarized a few new analogues of ISL in below (see Figure 2):

 

Cancers 13 00115 g002 550

Figure 2. Isoliquiritigenin (ISL) derivatives.

 

  • 4-C-β-D-glucosylated ISL (Figure 2a): Glucosylation of low molecular weight compounds have improve water solubility and bioavailability with a good inhibition of aldose reductase (AR)[33].

  • Synthetic isoliquiritigenin derivatives (BS5 and BS11 in Figure 2b,c): The compounds BS5 and BS11 with m-, p-dimethoxy, o-bromo phenyl group shows neuroprotective effects at 3 μM to 6 μM with higher viability (~80–100%)[32].

  • Robtein (ISL-derivative #10; Figure 2d): Robtein exhibited osteoclast differentiation and activation without any significant changes of viability or cytotoxicity[28].

  • 2′,4′-dimethoxy-4-hydroxychalcone (Figure 2e): shows in vivo antidiabetic activity[31].

  • 3′,4′,5′,4″-tetramethoxychalcone (TMC; Figure 2f): Introducing methylation of hydroxy groups significant increase cytotoxic activity in breast cancer[27], especially targeting on triple-negative breast cancer (TNBC)[29].

  • ISL-17 (Figure 2g): A fluorine atom was introduced to the structure of ISL named ISL-17 showed the anti-tumor activities in gastric cancer[28].

However, the poor bioavailability and water-solubility issues remain in clinical applications. Future studies are still needed to elucidate the ISL formulations that would be more suitable for human clinical trials.

4. ISL Docking Model

ISL had been reported to exert diverse biological properties, but the specific molecular interaction that underlies these activities has not been fully unveiled. Based on molecular docking analysis, many studies have proposed that ISL has a direct interaction in different molecules (Figure 3), such as SIRT1 [34]VEGF2 receptor[35], GRP78[36], FLT3[37], EGFR[38], IKKβ[39], Toll-like receptors (TLRs)[40], CK-2 (IC50: 17.3 µM)[41], H2R[42], COX-2[43], aromatase (Ki: 2.8 µM)[44][45], topoisomerase I [46] and DNMT1[47]. These docking results imply that the binding pocket is composed of hydrophobic regions and is stabilized by a hydrogen bond with its neighboring carbonyl group. The hydrogen bond interactions and π–π stacking contribute to a tight interaction with the binding site. These docking results provide valuable information about the binding interactions of ISL and the active site, although more studies are required to approve them. Using a bioassay-guided purification method, suggested that isolated ISL acts as a xanthine oxidase inhibitor (IC50: 55.8 µM; Ki: 17.4 µM) to avoid transplantation rejection and ischemia reperfusion damage [48]. In brief, multiple docking candidates indicate that ISL exhibits multiple biological properties and serves as a potential lead compound for developing new therapy in cancer treatment.

Cancers 13 00115 g003 550

Figure 3. Molecular docking models. Interactions are represented in green (hydrogen bonding), orange (π–π stacking), purple (sigma-π) dash lines and gray (hydrophobic interaction: Van der Waals). (a) VEGFR-2; (b) EGFR; (c) GRP78; (d) SIRT1; (e) IKKβ; (f) DMNT1; (g) CK-2; (h) COX-2; (i) FLT3; (j) H2R; (k) TOPI.

5. ISL Biology Effects

In targeting cancers, ISL possesses various biologic activities, such as anti-inflammation, antioxidation, antiviral, antidiabetic, neuroprotective effect, chemopreventive, and antitumor growth properties (Figure 4 and Figure 5). A selective cytotoxicity effect of ISL has been reported (Table 2 and Table 3), and the effective dose in tumor cell lines shows very little cytotoxic effect on normal cells. Most studies have claimed that ISL significantly inhibits the viability of cancer cell but has little toxicity on normal cells. For example, Wu et al. (2017) compared the human endometrial stromal cells (T-HESCs; as a control) and human endometrial cancer cell lines (Ishikawa, HEC-1A, and RL95-2 cells). Their results indicated that ISL inhibits the growth of cancer cells at concentrations below 27 μM, but has little effect on normal cells[49]. Na et al. (2018) claimed that ISL shows little toxicity on normal hepatocyte cell lines (AML-12); only when applied in concentrations of over 100 μM is ISL harmful to normal hepatocytes [50]. Most studies have focused on the cytotoxicity between tumor and normal cells, and the effects of ISL on normal cells remain unknown. As Peng et al. (2015) mentioned, further research on the target organ toxicity or side effects of ISL is needed. The safety of ISL is always one of the most important concerns that must be evaluated.

Cancers 13 00115 g004 550

Figure 4. Pharmacological effect of ISL. The scheme presents the biological effects of ISL and molecular mechanisms of ISL against cancer via various signal pathways.

Cancers 13 00115 g005 550

Figure 5. ISL-mediated regulation of molecular targets underlying anti-tumor effects, including tumor proliferation suppression, apoptosis induction, EMT/metastasis, epigenetic responses and sensitization to chemotherapy. Downward arrows (↓) represent downregulation while upward arrows (↑) represent upregulation. This figure was modified from[51].

Table 2. ISL influenced on normal cell lines.

Type Cell Line Result Ref
Breast MCF-10A
(0~50 µM)
(24 h)		 ISL had no significant influence on MCF-10A as human normal tissues. [36]
MCF-10A
(0~100 µM)
(24 h)		 ISL had limited inhibitory effects on the proliferation in normal cell and did not show the chemosensitization effect with epirubicin. [52]
H184B5F5/M10
(0.1~10 µM)
(6~48 h)		 ISL did not influence the normal cell viability at the at 0.1~10 µM. [53]
Lung HELF
(24~72 h)		 Both pure drug of ISL and nanosuspension showed low toxicity to normal cells. [16]
Hepatocyte AML-12
(0~200 µM)
(24 h)		 5~50 μM of ISL increased cell proliferation, strong cytotoxicity was observed over 100 μM. [50]
Uterus
Endometrium		 T-HESCs
(5~100 µM)
(24~48 h)		 The viability of T-HESCs showed significant changes when ISL concentration over 75 μM was applied. [49]
Gastric GES-1
(20 µM)
(48 h)		 ISL exhibited a negligible effect on cell growth and cell viability exceeded 70%. [28]
Endothelia HUVEC Over 10 µM of ISL is nontoxic with inhibiting the VCAM-1 and E-selectin. [54]
Small intestine IEC-6
(10~100 µM)
(24 h)		 No effect was observed in IEC-6 cells. [55]
Oral SG cell
(25~400 μM)
(24 h)		 The half maximal effective dose (IC50) of ISL is 386.3 ± 29.7 μM. [56]
Brain H22 ISL had the potential to against glutamate-induced neuronal cell death (neuroprotective effect) [32]

able 3. Different pathways of various cancers regulated by ISL.

Type of Cancer Cell Testing Range/IC50 Signaling Pathways Effect of ISL
(In Vitro)		 Ref
Breast cancer MCF-7 Testing conc: 10 nM~10 µM
(5 days; 10 nM is sufficient)
  • ⇧Presenilin2 (pS2) mRNA level
  • ⇩Proliferation
  • ⇩Estrogen receptor (ERα)
 [57]
MCF-7
MDA-MB-231		 Effective conc: 25 µM and 50 µM
(24 h)
  • ⇧WIF1
  • ⇩DNMT1
  • ⇩β-catenin (⇩Metastasis)
  • ⇩Wnt
  • ⇩G0/G1 (Cell cycle arrested)
  • ⇩Cyclin D1 (⇧Apoptosis)
  • ⇩Survivin
  • ⇩c-myc
  • ⇩Oct-4
 [41]
MCF-7
MDA-MB-231
HUVEC		 Testing conc.: 0, 20, 40, 60, 80,
100 µM
  • ⇧HIF-1α proteasome degradation
  • ⇩VEGF expression
  • ⇩Cancer growth via VEGF/VEGFR-2
  • ⇩Neoangiogenesis via VEGF/VEGFR-2
 [58]
Tumor cell line:
MCF-7 IC50 estimated = ~33.39 µM
MDA-MB-231 IC50 estimated = ~35.64 µM
(48 h)
HUVEC IC50 estimated = ~75.48 µM
PMA-induced
COX-2 in MCF-10A		 Effective conc: 0.1 µM and 10 µM
(24 h; 1 µM is sufficient.)
  • ⇩COX-2 expression modulated ERK-1/2 signaling
 [59]
BT549
MDA-MB-231		 Effective conc.: 10, 20, 40 µM (12 h)
  • ⇧Cleaved caspase-3 & 9 (⇧Apoptosis)
  • ⇩COX-2 (⇩Metastasis)
  • ⇩CYP 4A, ⇩PGE2, ⇩PLA2
 [60]
MDA-MB-231
Hs-578T		 Effective conc.: ~20 µM
  • ⇧RECK
  • ⇩miR21 and ⇩MMP-9 (⇩Invasive)
 [61]
Breast cancer MCF-7
MDA-MB-231		 Testing conc.: 0, 5, 10, 20 µM
  • ⇩mRNA level of phospholipase A2 (PLA2), cyclooxygenases-2 (COX-2) and cytochrome P450 (CYP) 4A
  • ⇩Cancer growth (⇩Arachidonic acid metabolism)
  • ⇧Apoptosis
  • ⇩PI3K/AKT pathway
 [62]
Tumor cell line:
MCF-7 IC50 = 10.08 µM
MDA-MB-231 IC50 = 5.5 µM
(48 h)
MCF-7
MDA-MB-231		 Testing conc.: 0, 6.25, 12.5, 25, 50,
100 µM
  • ⇧PTEN (⇧Apoptosis)
  • ⇧Bax (⇧Apoptosis)
  • ⇧Caspase 9
  • ⇧MMP-7 (⇩Lung metastasis)
  • ⇩miR374a (⇩Metastasis and ⇩proliferation)
  • ⇩Bcl-2
  • ⇩p-GSK3β, AKT
  • ⇩β-catenin (⇩Migration and ⇩invasion)
 [63]
Tumor cell line:
MCF-7 IC50: 32.66 µM
MDA-MB-231 IC50: 22.36 µM
(24 h)
MDA-MB-231
Hs-578T		 Effective conc.: 10 µM and 20 µM
  • ⇧PIAS3
  • ⇩miR21 and ⇩STAT3 (⇩Invasion)
 [64]
MCF-7
MDA-MB-231
BT549
MCF-10		 Testing conc.: 1, 5, 10 and 25 µM
  • ⇧Proteasome degradation
  • ⇧β-catenin degradation
  • ⇧Apoptosis via ⇩ miR-374a
  • ⇧Chemosensitivity
  • ⇩β-catenin /ABCG2/ GRP78 (⇩Proliferation)
  • ⇩GSK-3β phosphorylation via AKT pathway (⇧Chemosensitization)
  • ⇩CD44+CD24−, Survivin, Oct-4,
  • ⇩Cyclin D1
 [36]
Tumor cell lines:
MCF-7 IC50 estimated: ~33.0 µM
MDA-MB-231 IC50 estimated: ~21.2 µM
BT549 IC50 estimated: ~18.1 µM
(24 h)
Normal cell line:
MCF- 10A IC50 estimated: ~80.51 µM
(24 h)
Breast cancer MCF-7
MDA-MB-231
H184B5F5/M10		 Effective conc: 25 µM and 50 µM
(48 h) Tumor cell lines:
MCF-7
MDA-MB-231
  • ⇩VEGF (⇩Anti-angiogenesis)
  • ⇩HIF-1α (⇩Proliferation)
  • ⇩MMP-9 (⇩Migration)
  • ⇩PI3K
  • ⇩NF-kB
  • ⇩p38
 [65]
Normal cell line:
H184B5F5/M10
(ISL did not influence the viability)
MCF-7
MCF-7/ADR MCF-10A		 Tumor cell lines:
MCF-7 IC50 estimation: ~59.39 µM
MCF-7/ADR IC50 estimation: ~38.86 µM
(24 h)
  • ⇧ULK1 (⇧Autophagy)
  • ⇧LC3-II (⇧Chemosensitization)
  • ⇩miR-25(⇧Autophagy)
  • ⇩ABCG2
 [53]
Normal cell line:
MCF-10A
ISL (at 100 µM) had limited inhibitory effects on the proliferation
MDA-MB-231 Testing conc.: 0, 10, 25, 50 µM
MDA-MB-231 IC50 estimated: ~24.23 µM
(48 h)
  • ⇧Bax
  • ⇧Caspase-3 and ⇧PARP
  • ⇧ p62, ⇧Beclin1, and ⇧LC3 (⇧Autophagy)
  • ⇧Caspase-8 (⇧Autophagy and ⇧apoptosis)
  • ⇩Cyclin D1 (⇩Proliferation)
  • ⇩Bcl-2
  • G1 arrest
 [66]
MCF-7aro Testing conc.: 0, 0.625, 1.25, 2.5, 5, 10 µM MCF-7aro IC50: 2.5 µM
(24 h)
  • ⇩mRNA level of aromatase
  • ⇩CYP19 promoters I.4, I.3 and II activity
 [44]
Colon cancer HT29 HT29 ED50: 11.1 µg/mL (42.32 µM)
  • DNA demethylating effect
 [67]
HT29 Testing conc.: 0, 5,10, 20, 30, 40,
50 µM
40 µM was applied; (24 h)
  • ⇧DR5(⇧Apoptosis)
  • ⇩PI3K/AKT pathway
 [68]
HCT116
HT29
SW480		 Testing conc.: 0,10, 20, 30, 40 µM
HCT116 IC50 estimated = ~42.41 µM
Working conc.: 30 or 40 µM; (24 h)
  • ⇧Apoptosis
  • ⇧p62/SQSTM1 (⇧Autopage cell death)
  • ⇧PARP cleavage
  • ⇩Caspase-8 activation (⇧Apoptosis)
 [69]
HCT116 Testing Conc.: 0, 2.5,5, 10, 20, 40, 80, 160 µM
HCT116 IC50 estimated: ~78.78 µM (48 h)
HCT116 IC50 estimated: ~53.97 µM (72 h)
HCT116 IC50 estimated: ~44.8 µM (96 h)
  • ⇧NAG-1 expression mediated EGR-1, p53, ATF-3, Sp1 and PPARγ
  • ⇧Apoptosis (Caspase dependent pathway)
  • ⇩Bcl-2 and Bcl-xL
  • G2 phase cycle arrested
 [70]
CT26 Testing Conc.: 0, 10, 20, 40, 60, 80 µM
CT26 IC50 estimated = ~54.48 µM
  • ⇧Serum nitric oxide, ⇧Lipid peroxidation levels and ⇧GSH levels
  • ⇩ ROS
  • ⇩Proliferation
  • ⇩COX-2 (⇧Apoptosis)
 [71]
Colon26
RCN9
CoLo-320DM		 Testing Conc.: 0, 5, 25, 100 µM (24,
48 h)
Colon26 IC50 estimated = ~17.55 µM
(24 h)
Colon26 IC50 estimated = ~12.59 µM
(48 h)
RCN9 IC50 estimated = ~41.73 µM (24 h)
RCN9 IC50 estimated = ~18.21 µM (48 h)
CoLo-320DM
IC50 estimated = ~23.10 µM (24 h)
CoLo-320DM
IC50 estimated = ~10.82 µM (48 h)
  • ⇧Apoptosis
  • ⇩PGE2 depends on ⇩COX-2 expression
  • ⇩NO via (⇩iNOS)
 [72]
Colon cancer HCT116 Applied 20 µM
(48 h)
  • ⇧Bax and ⇧cleaved caspase-3 (⇧Apoptosis)
  • ⇩PI3K/AKT signaling pathway
  • ⇩Cancer proliferation, ⇩Invasion and ⇩migration
  • ⇩Bcl-2, p-AKT, p-mTOR, CyclinD1
 [73]
Caco-2/TC-7 Caco-2/TC-7 EC50: 42 μM
  • ⇧ HBD3 (human β-defensin-3)
  • ⇧EGFR-MAPK pathway
 [74]
Ovary cancer SKOV3
OVCAR5
ES2		 Testing conc.: 2, 4, 8, 16, 32, 64, and 100 µM
SKOV3 IC50: 83.2 µM (72 h)
OVCAR5 IC50: 55.5 µM (72 h)
ES2 IC50: 40.1 µM (72 h)
Effective Conc.: 10 µM
  • ⇧E-cadherin
  • ⇩ZEB1 mRNA
  • ⇩Vimentin and ⇩N-cadherin (⇩EMT)
  • ⇩TGF-β
 [75]
SKOV3
OVCAR5		 Testing conc.: 0, 1, 5, 10, 20, 25, 50, 75, and 100 µM
OVCAR5 IC50: 11 µM (48 h)
ES2 IC50: 25 µM (48 h)
  • ⇧Cleaved PARP, ⇧cleaved caspase-3, ⇧ Bax/Bcl-2 ratio, ⇧LC3B-II, and ⇧Beclin-1
  • ⇧CDK2
  • G2/M phase arrest
  • ⇩Cyclin B1
 [76]
Antral follicle culture (female CD-1 mic) Testing conc.: 0.6, 6, 36, and 100 μM
  • ⇧STAR
  • ⇩mRNA levels of cytochrome P450 steroid 17 α-hydroxylase 1 (⇩CYP17A1), cytochrome P450 aromatase (⇩CYP19A1)
 [77]
SKOV3 OVCAR3 Testing conc.: 5~80 μM
30 μM applied
  • ⇧GSK3β
  • ⇩p-AKT and p-mTOR
  • ⇩P70/S6K, Cyclin D1
  • ⇩Wnt3a, ⇩p-ERK, ⇩PI3K/AKT/mTOR
 [78]
SKOV3 N.A.
  • ⇧ER stress,⇧ p-eIF2α, GADD153/CHOP, GRP78, XBP1 expression, and cleavage of ATF6α (⇧Apoptosis and ⇧autophagy)
 [76][79]
Lung cancer H1299
H1975
A549		 H1299 IC50 estimated: ~36.78~46.08 µM
H1975 IC50: 48.14 µM
A549 IC50: 75.08 µM (48 h)
  • ⇩Src kinase activity (⇩Proliferation and ⇩migration)
 [9]
A549 A549: applied 20 µM (24 h)
  • ⇧Bax and ⇧caspase-3
  • ⇧E-cadherin
  • ⇩Bcl-2
  • ⇩mTOR (⇩PI3K/AKT pathway)
  • ⇩P70, ⇩Cyclin D1, ⇩N-cadherin and ⇩vimentin
 [80][81]
RAW 264.7 Testing conc.: 5, 10, 20 µM for (Pretreated with 10mM of t-BHP for 18 h)
RAW 264.7 (treated with t-BHP)
EC50 = 10 µM (18  h)
  • ⇧AMPK/Nrf2 signaling
  • ⇧ Nrf2 and its target enzymes (e.g., ⇧HO-1, ⇧GCLM, ⇧GCLC, and⇧ NQO1)
  • ⇩iNOS and ⇩COX-2
  • ⇩TNF-α, ⇩IL-1β, and ⇩IL-6
  • ⇩NLRP3 in a Nrf2-dependent pathway
  • ⇩NF-κB (p65) via Nrf2-independent pathway
 [82]
Calu-3 Calu-3 cells were infected with PR8/H1N1 virus; [EC50] = 24.7 μM
  • ⇧PPARγ (⇩Influenza virus infection)
  • ⇧TNF-α, ⇧IL-1β, and ⇧IFN-β
 [83]
H1650
H1975
A549		 H1650 IC50 estimated: ~26.88 µM (24 h)
H1975 IC50 estimated: ~8.92 µM (24 h)
A549 IC50 estimated: ~46.7 µM (24 h)
  • ⇧Bim (⇧Apoptosis)
  • ⇩Bcl-2, ⇩ p-AKT, and ⇩p-ERK1/2
 [38]
A549 A549 IC50: 0.05 mg/mL (~191.21 µM ~117 µM)
  • ⇧p53, ⇧p21 and ⇧Bax
  • Arrest at G2/M phase
  • ⇩PCNA, ⇩ MDM2, ⇩p-GSK-3β, ⇩p-AKT, ⇩p-c-Raf, ⇩p-PTEN, ⇩caspase-3, ⇩pro-caspase-8, ⇩pro-caspase-9, ⇩PARP, and ⇩Bcl-2
 [84]
Lung cancer guinea-pig tracheal smooth muscle N.A.
  • ⇧cGMP/PKG (⇧BKCa channels opened)
  • ⇩PDEs (⇩[Ca2+]i led tracheal relaxation)
 [85]
A549 A549 IC50: 27.14 µM
  • ⇧p53 and ⇧p21/WAF1
  • ⇧Apoptosis via Fas/FasL apoptotic system
  • Arrested at G1 phase (⇩Proliferation)
 [86]
A549 A549 IC50: 18.5 µM
  • ⇧p21CIP1/WAF via p53 independent pathway
  • G2/M arrest(⇩Proliferation)
 [87]
AML
(acute myeloid leukemia)		 HL-60 HL-60 ED50: 5.5 µg/mL (~21.46 µM)
5.00 µg/mL = 19.5 µM (72 h)
  • ⇧DNA demethylation
 [61]
MV4-11
MOLM-13
OCI-LY10		 MV4-11 IC50: 3.2 + 1.2 µM; MOLM-13 IC50: 4.9 + 2.1 µM OCI-LY10 IC50: 20.1 ± 6.7 µM
(72 h)
  • ⇧STAT5
  • ⇩FLT3/Erk1/2
 [31]
LCLs Testing conc.: 0, 20, 40, 60, 80, 100, 120, 140 µM
LCLs IC50 estimated: 40~65 µM (24 h)
Applied 50 µM for studies.
  • ⇧HMOX1, ⇧SLCO2B1, and⇧OKL38
  • ⇩CDK5R1 and CDC45L via p53 pathway
 [80]
HL-60 Testing conc.: 1~15 µg/mL
(3.9 µM~58.54 µM)
HL-60 IC50 estimated: ~40.42 µM
(72 h)
  • ⇧CD11b and ⇧CD14 expression (⇩Proliferation)
  • ⇩iROS (⇧monocytic differentiation)
 [81]
RAW264.7 Testing conc.: 20 and 50 μM
  • ⇩TRIF-dependent pathway
  • ⇩NF-κB and ⇩IRF3
 [88]
AML
(acute myeloid leukemia)		 RAW264.7 Testing conc.: 50 and 100 μM
  • ⇧IRF3
  • ⇩TBK1 kinase activity
  • ⇩IFNβ production
 [89]
HL-60 Testing conc.: 2.5~20 μg/mL
(3.9 µM~78.05 µM)
(Working conc.: 72 µM)
  • ⇧CD11b and ⇧CD14 mRNA expression
  • ⇧gp91phox and ⇧p47phox
  • ⇧NADPH oxidase (⇩ROS)
  • ⇩ROS (⇧HL-60 differentiation)
 [90]
HL-60 Testing conc.: 2.5~10 μg/mL
(3.9 µM~39.0 µM)
  • ⇧CD11b and ⇧CD14 (⇧Monocyte differentiation via Nrf2/ARE)
  • ⇧Horseshoe-shaped nuclei
  • ⇧Lipid peroxidation (MDA) level
  • ⇩GSH/GSSG ratio (mRNA expression of ⇧CAT, ⇧NQO-1, ⇧Thioredoxin reductase and ⇧TRx)
 [91]
Jurkat
J-Jhan
J16
HUT78
Karpas 45		 Jurkat IC50: 0.49 ± 0.12 nM (72 h)
J-Jhan IC50: 1.55 ± 1.12 nM (72 h)
J16 IC50: 5.25 ± 1.12 µM (72 h)
HUT78 IC50: 11 ±13.5 µM (72 h)
Karpas 45 IC50: 6.61 ± 1.07 µM (72 h)
  • ISL did not have a correlation with doxorubicin (DOX) and methotrexate (MTX) in genomic profiles.
  • ISL is a valuable adjunct for cancer therapy, especially targeting on drug-resistant tumors.
 [92]
CCRF-CEM CCRF-CEM IC50: 18.38 μM (24~72 h)
  • ⇩Mitochondrial membrane potential disruption
  • ⇧DNA damage
  • G2/M arrest (⇩Proliferation)
  • ⇩Cytochrome c
 [93]
AML
(acute myeloid leukemia)		 Human monocyte model THP-1 N.A.
  • ⇧DNCB-induced MAPK activation
  • ⇧CD86 and ⇧CD54
  • ⇩DNCB-induced pro-inflammatory cytokines (⇩TNF-α, ⇩IL-6 and ⇩IL-4)
  • ⇩p38-α and ⇩ERK activation
 [94]
Melanoma A375
A2058		 Testing Conc: 0, 10, 20, 40,
80 µM
A375 IC50: 21.63 µM (24 h)
A2058 IC50: 20.75 µM (24 h)
  • ⇧C-PARP, ⇧Bax, ⇧ cleaved-caspase-3(⇧Apoptosis)
  • ⇩Proliferation
  • ⇩Bcl-2
 [95]
B16F0 N.A.
  • ⇧B16F0 differentiation
 [96]
A375 Testing Conc.: 0, 5, 10, 15 μg/mL
(15 μg/mL = 58.53 µM)
A375 IC50 estimated: ~48 µM
  • ⇧Melanin content (⇧Melanogenesis)
  • ⇧Tyrosinase (TYR) activity
  • ⇧O2 consumption rate (OCR)
  • G2/M cell cycle arrest
  • ⇩mRNA level of GLUT1 and HK2
  • ⇩mTOR, ⇩p-mTOR, ⇩RICTOR, ⇩p-AKT, ⇩p-GSK3β
 [97]
A375 40 μg/mL: 69.86%
60 μg/mL: 92.22%
A375 IC50 estimated: ~73 µM (24 h)
  • ⇧Cleaved PARP and ⇧Cleaved caspase-3
  • ⇩Mitochondrial membrane potential
  • ⇩mitoNEET
 [98]
Melanoma B16F0 Testing Conc.: 20, 40, 60 and
80 μg/mL
B16F10 IC50 estimated: 35 μg/mL
(~41.576 μM; 24 h)
B16F10 IC50 estimated: 22 μg/mL
(~86.77 μM; 48 h)
  • ⇧ROS (⇧Apoptosis)
  • Restart TCA cycle
  • ⇩HIF-1α (Alleviating hypoxia)
  • ⇩Lactate production
  • ⇩Glucose uptake and glycolysis
 [99]
B16F10 Testing Conc.: 5, 10, 15, 20, and
25 μg/mL
B16F10 IC50 estimated: ~19 μg/mL
(~74.595 μM; 24 h)
B16F10 IC50 estimated: ~10.5 μg/mL
(~41.576 μM; 48 h)
  • ⇧TYR Activity
  • ⇧Melanin Biosynthesis
  • ⇧ROS
  • ⇩Colony formation
  • ⇩Cell proliferation
 [100]
ARH-77
U266
MPC-11 SP2/0
CZ-1
RPMI8226		 ARH-77 IC50: ~13.54 µM
MPC-11 IC50: ~4.45 µM
SP2/0 IC50: ~22.91 µM
CZ-1 IC50: ~13.93 µM
U266 IC50: ~8.62 µM
RPMI8226 IC50: ~9.09 µM
IC50 of ISL was < 4 μg/mL (48 h)
  • ⇧Cleavage caspase-3
  • ⇩IL-6
  • ⇩p-ERK and ⇩p-STAT3
  • ⇩Bcl-2, ⇩Bcl-XL and ⇩pro-caspase-3
 [101]
SK-MEL-2
HaCaT		 Testing Conc.: 0, 1, 4, and 8 µM
SK-MEL-2 cells and HaCaT cells (48 h) treated less than 8 µM showed no cytotoxic effects
  • ⇧p-p38
  • ⇩Tyrosinase (⇩Tyrosine kinase)
  • ⇩ TRP-1, ⇩DCT, ⇩Rab27a and ⇩Cdc42
  • ⇩ ERK pathway (⇩Degradation of MITF)
 [102]
Melanoma B16 mouse melanoma 4A5 cells Testing 150 and 200 µM
(18 and 24 h)
  • ⇧Apoptosis (p53 independent pathway)
  • ⇧Bax
  • ⇩Cell proliferation
  • ⇩Glucose transmembrane transport
 [103]
HCC/Hepato-ma Hep3B Hep3B IC50: 42.84 + 2.01 μM
50 μM applied (48 h)
  • ⇧P21, ⇧P27
  • G1/S cell cycle arrest (⇩Proliferation)
  • ⇩Cyclin D1
  • ⇩PI3K/AKT pathway
  • ⇧E-cadherin, ⇩Vimentin and ⇩N-cadherin (⇩Migration and ⇩metastasis)
 [104]
HepG2
Hep3B		 Testing conc.: 20, 40, 60, 80, and
100 μM (18 h)
HepG2 IC50: 27.71 μM
Hep3B IC50: 35.28 μM
  • ⇧ MAPK/STAT3/NF-κB (⇧Apoptosis)
  • ⇧ ROS accumulation
  • ⇧Phosphorylated c-Jun N-terminal kinase (JNK), ⇧P21, ⇧p38 kinase
  • G2/M arrest (⇩Proliferation)
  • ⇩p-ERK, ⇩p-STAT3, and ⇩NF-κB (p65)
  • ⇩Cyclin B1, ⇩CDK1/2, and ⇩p27
 [105]
HepG2 Testing conc.: 1, 5, 10, 20 μg
HepG2 IC50 estimated: ~88.46 μM (24 h)
HepG2 IC50 estimated: ~31.07 μM (48 h)
  • ⇧p53, ⇧p21/WAF1, ⇧ Fas/APO-1 receptor, Fas ligand, ⇧Bax and ⇧NOXA (⇧Chemopreventive effect)
  • G2/M-phase arrest
 [106]
HepG2 HepG2 IC50: 10.51 μg/mL (~39 μM;
48 h)
  • ⇧IkB
  • ⇩NF-κB, Bcl-XL, c-IAP1/2
 [107]
HCC/Hepato-ma SNU475 SNU475
IC50: 0.243 + 0.21 mM
  • ⇩ DNA cleavage reaction (Stabilized DNA)
  • ⇩TOP I activity(ISL-TOP I interaction: 0.18 + 0.12 mM)
 [58]
Hepa 1c1c7 Hepa 1c1c7 IC50: 36.3 μM
  • ISL is a chemopreventive reagent
 [108]
Hep3B Hep3B IC50: 50.8 μM
  • ⇩CK2 activity (CK2 IC50: 17.3 uM)
 [43]
SK-Hep-1 SK-Hep-1 IC50: 19.08 μM
  • ⇩ Proliferation
 [109]
PC-3
22RV1		 Testing conc: 0, 1, 10, 25, 50, and 100 μM)
PC-3 IC50: 19.6 μM (48 h)
22RV1 IC50: 36.6 μM (48 h)
  • ⇧Apoptosis
  • G2/M cell cycle arrest
  • ⇩Cyclin B1, ⇩CDK1 (p-Thr14, p-Tyr15, and p-Thr161)
 [110]
Prostate cancer C4-2
LNCaP
IEC-6		 10~100 μM (24 h)
C4-2 IC50: 87.0 μM
  • ⇧AMPK and ⇧pERK (⇩Proliferation)
  • ⇧p-p38
  • ⇩Psi(m) (⇧Apoptosis)
 [59]
DU145 Applied conc.: 5~20 μM
  • ⇧p-CDC2 (Tyr15) and ⇧Cyclin B1
  • ⇧G1 phase
  • ⇧p27KIP1
  • G2/M cell cycle arrest
  • ⇩CDC25C
 [111]
DU145 Applied conc.: 0~20 μM
  • ⇩JNK/AP-1 signaling
  • ⇩VEGF, ⇩integrin-α2, ⇩ICAM and ⇩VCAM
  • ⇩Invasion and ⇩metastasis via ⇩µPA, ⇩MPP-9 and ⇩AP-1
 [112]
DU145 Applied conc.: 0~20 μM
  • ⇩PI3K/AKT and ErbB3 pathway (⇩Proliferation)
  • ⇩HRG-β-induced ErbB3 signaling (⇩ErbB3)
 [113]
Prostate cancer MAT-LyLu
DU145		 Applied conc.: 0~20 μM
MAT-LyLuIC50 estimated:
~13.74/5.67/5.01 µM
DU145 IC50 estimated:
~56.87/31.49/17.60 µM
(24 h/48 h/72 h)
  • ⇧ Fas ligand (FasL), ⇧Fas, ⇧Cleaved caspase-8 and ⇧tBid (⇧Apoptosis)
  • lic>249) ⇧Cytochrome c and Smac/Diablo
 [114]
DU145 LNCaP Testing conc.: 0, 5, 10, 15, and 20 μM
DU145 IC50 estimated: ~10.561 µM (48 h)
LNCaP IC50 estimated: ~10.775 µM (48 h)
  • ⇧GADD153 mRNA
  • S and G2/M arrest
 [115]
Cervical cancer Ca Ski
SiHa
HeLa
C-33A		 Testing conc: 10, 20, 40, and 80 µM
Ca Ski IC50 estimated: 39.09 μM (72 h)
SiHa IC50 estimated: 53.76 μM (72 h)
HeLa IC50 estimated: 58.10 μM (72 h)
C-33A IC50 estimated: 32.83 μM (72 h)
  • ⇧p53, ⇧p21, ⇧Bax
  • ⇧Cleavage of caspase-9, ⇧caspase-3, ⇧PARP and ⇧caspase -8
  • ⇩Bcl-2
 [116]
HeLa Testing conc: 2, 5, 10, 30, 40, and
60 μg/mL
HeLa IC50 estimated: ~21.24 μM (24 h)
  • ⇧ROS
  • ⇧p-eIF2α, ⇧GRP78 level (⇧ER stress)
  • ⇧Caspase-12
  • G2/M cell cycle arrest (⇩Proliferation)
  • ⇩Bcl-2
 [117]
HeLa HeLa IC50: 9.8 μM (48 h)
  • ⇧p53
  • ⇧p-Chk2, ⇧p-cdc25C, and ⇧p-cdc2
  • G2/M cell cycle arrest
  • ⇩p-p53 (Serine15)
  • ⇩Bcl-2, Bcl-XL
  • ⇩Cyclin B, ⇩cyclin A, ⇩cdc2, and ⇩cdc25C
 [118]
Gastric cancer MKN28 MKN28 IC50: ~20.84 µM (48 h)
  • ⇧Beclin 1
  • ⇩p62 (⇧Autophagy)
  • ⇩p-AKT and ⇩p-TOR (⇧Apoptosis)
 [119]
MKN-45 5 µM applied
  • ⇩H2R and ⇩c-Fos/c-Jun
 [120]
MGC-803 0.11 g/L applied (24 h)
  • Calcium- and delta psi(m)-dependent (⇧Apoptosis)
 [121]
SGC-7901 BGC-823 BGc-823 IC50: 23.18 µM (48 h)
SGC-7901 IC50: 12.91 µM (48 h)
  • ⇧G2/M cell cycle arrest (⇩Proliferation)
  • ⇧Cleaved-PARP, ⇧Bcl-2 and ⇧Bax (⇧Apoptosis)
  • ⇧LC3B II and⇧ Beclin 1(⇧Autophagy)
  • ⇩PI3K/AKT/mTOR
 [34]
Uterine leiomyoma Leiomyma
Myomentrium		 Testing conc: 0, 10, 20, 50 µM
Leiomyma IC50 estimated = ~39.33 µM
Myomentrium IC50 estimated =
~698.8 µM
(48 h)
  • ⇧FAS ligand expression(⇧Apoptosis)
  • ⇧p21Cip1/ Waf (⇧Apoptosis via p53-dependent)
  • ⇧Caspase-3 activation
  • subG1 and G2/M arrest (⇩Proliferation)
  • ⇩Bcl-2, ⇩cdk 2/4, and ⇩E2F
 [122]
Osteosarcoma U2OS Testing conc: 5, 10, and 20 µM
20 μM applied
  • ⇧Bax and ⇧caspase-3 (⇧Apoptosis)
  • ⇧p53, ⇧p21 and ⇧p27
  • ⇩Bcl2,⇩PI3K/AKT/mTOR pathway
  • ⇩p70, ⇩Cyclin D1, ⇩Bcl‑2, ⇩MMP-2/⇩MMP-9
 [123][128]
Saos‑2
MC3T3-E1		 Saos‑2 IC50 estimated = ~24.23 μM
30 μM applied
Glioma SK-N-BE(2) IMR-32 Effective conc. > 5 µM
  • ⇧ROS (⇧Necrosis)
 [125]
U87 U87 IC50: 6.3 µM
  • ⇧Caspase-3
  • ⇩TOP I
 [124]
PC12 PC12 IC50: 17.8 ± 1.8 μM
  • ⇧Caspase-9, ⇧caspase-3, ⇧ caspase-7, ⇧Bax, ⇧Bim, and ⇧cytochrome c (⇧Apoptosis)
  • ⇧Beclin-1 and ⇧LC3 (⇧Autophagy) ⇩Bcl-2 and ⇩Bcl-x
 [126]
Bladder cancer T24 Effective conc.: 30 and 70 µg/mL
(24 h)
  • ⇧Bax, ⇧Bim, ⇧Apaf-1, ⇧Caspase-9, ⇧Caspase-3, and ⇧CDK2 activity
  • ⇩ΔΨm and ⇩Bcl-2
 [127]
Oral
squamous cell carcinomas (OSCC)		 SG
SAS-CSCs
OECM-1		 SG cells IC50: 386.3 ± 29.7 μM
SAS-CSCs IC50: 144.9 ± 25.7 μM
OECM-1-CSCs IC50: 104.5 ± 26.2 μM
  • ⇩GRP78
  • ⇩CSCs properties
  • ⇩ABCG2 expression
 [54]

ote: The ‘’IC50 estimated’’ indicated Data extracted from published figures using Web Plot Digitizer (https://automeris.io/WebPlotDigitizer), then analyzed IC50 by “Quest Graph™ IC50 Calculator.” AAT Bioquest Inc, 27 October 2020, https://www.aatbio.com/tools/ic50-calculator [133].

 
 
 

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Shih-Min Hsia
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