Diarylpentanoid, a curcumin analog, inhibits malignant meningioma growth in both in vitro and in vivo models

Abstract

Background: Malignant meningioma metastasizes systemically, primarily due to its role in epithelial-mesenchymal transition. Although the prognosis is extremely poor, drug development efforts have been limited, because this tumor is categorized as a rare form.

Aim: To examine growth suppressive effect of GO-Y030, a diarylpentanoid curcumin analog, (1E,4E)-1,5-bis [3,5-bis (methoxymethoxy) phenyl] penta-1,4-dien-3-one against the malignant meningioma.

Methods: The growth suppression of malignant meningioma cells by GO-Y022 and GO-Y030 were examined, using IOMM-Lee and HKBMM cell lines. Male nude mice aged eight weeks, specifically BALB/cSlc-nu/nu mice received a subcutaneous inoculation of IOMM-Lee (10⁷ cells/site) on their back and 30 μg/kg of recombinant hepatocellular growth factor (HGF) was injected into the tumor every three days. After confirmed the growth tumor mass, 500 μL of GO-Y030 diluted with PBS were administrated intraperitoneally daily at doses of 1 mg/kg and 2 mg/kg, respectively.

Results: GO-Y030 exhibits a growth inhibitory effect on malignant meningioma cell lines, IOMM-Lee and HKBMM ranging from 0.8-2.0 μM in vitro. Notably, GO-Y030's inhibitory effect is about 10 to 16^th times more potent than that of curcumin, which has previously demonstrated potential in combating malignant meningioma. In mouse models, the intraperitoneal administration of GO-Y030 effectively suppresses the growth of malignant meningioma tumors that have been inoculated in the back (P = 0.002). High-performance liquid chromatography analysis has confirmed the distribution of GO-Y030 in the bloodstream and brain tissue. Moreover, GO-Y030 demonstrates the ability to significantly suppress HGF (P < 0.01), nuclear factor kappa B (P < 0.001), and N-cadherin (P < 0.001), all of which contribute to the epithelial-mesenchymal transition.

Conclusion: GO-Y030 holds promise as a potent compound for the systemic inhibition of malignant meningioma. GO-Y030 has higher tumor growth inhibitory effect against meningiomas than curcumin, which is known to have antitumor activity through multi-molecular target control resulting in apoptosis induction. GO-Y030 controls at least three molecules of HGF, nuclear factor kappa B, and N-cadherin.

Keywords: Curcumin; Diarylpentanoid curcumin analog; Hepatocellular growth factor; Malignant meningioma; N-cadherin; Nuclear factor kappa B.

Figure 1

Chemical structures of curcumin, GO-Y022 and GO-030.

Figure 2

Inhibition of meningioma growth by GO-Y030 in vitro. A: The growth inhibition of IOMM-Lee; B: The growth inhibition of HKBMM.

Figure 3

GO-Y030’s inhibitory effect on meningioma growth in vivo. A: The treatment schedule for the mouse model included intratumor (iT) hepatocellular growth factor administration every 3 days and daily intraperitoneal (ip) administration of GO-Y030; B: Relative tumor volume, with day 1, is set as 100%. GO-Y030 was administered at either 1 mg/kg mouse weight or 2 mg/kg indicated in orange or grey, respectively. The control was indicated in blue. Notably, GO-Y030 significantly suppressed tumor growth. ^aP and ^bP indicate the P values between the control and 1 mg/kg, and between the control and 2 mg/kg, 0.041 and 0.002, respectively. There was no significance between the 1 mg/kg and 2 mg/kg. ^cP = 0.059. The open circle represents the averages of 5 tumors, and the vertical bar depicts the standard deviation. HGF: Hepatocellular growth factor.

Figure 4

Inhibition of molecular targets in meningioma cell lines (IOMM-Lee) with GO-Y030 in vitro. A: Hematoxylin and eosin (HE) stains of IOMM-Lee treated with DMSO alone (control); B: Immunohistochemistry (IHC) of the N-Cadherin (N-Cad) in the control; C: IHC of the hepatocellular growth factor (HGF) in the control; D: IHC of nuclear factor kappa-B p65 (NF-kB) in the control; E: HE stains of IOMM-Lee treated with GO-Y030 at twice concentration of the 50% inhibitory concentration (IC₅₀ × 2); F: IHC of the N-Cad in IOMM-Lee treated with GO-Y030 at IC₅₀ x 2; G: IHC of NF-kB in IOMM-Lee treated with GO-Y030 at IC₅₀ × 2; H: IHC of the HGF in IOMM-Lee treated with GO-Y030 at IC₅₀ × 2; I: The percentage of normal appearance cells in IOMM-Lee treated with GO-Y030 at IC₅₀ × 2. J: The percentage of positive cells for N-Cad in IOMM-Lee treated with GO-Y030 at IC₅₀ × 2; K: The percentage of positive cells for NF-kB in IOMM-Lee treated with GO-Y030 at IC₅₀ × 2; L: The percentage of positive cells for HGF in IOMM-Lee treated with GO-Y030 at IC₅₀ × 2.

Figure 5

Inhibition of molecular targets in meningioma cell lines (HKB-MM) with GO-Y030 in vitro. A: Hematoxylin and eosin (HE) stains of HKBMM treated with DMSO alone (control); B: Immunohistochemistry (IHC) of the N-Cad in the control of HKBMM; C: IHC of the hepatocellular growth factor (HGF) in the control of HKBMM; D: IHC of NF-kB in the control of HKBMM; E: HE stains of HKBMM treated with GO-Y030 at IC₅₀ × 2; F: IHC of the N-Cad in HKBMM treated with GO-Y030 at IC₅₀ × 2; G: IHC of NF-kB in HKBMM treated with GO-Y030 at IC₅₀ × 2; H: IHC of the HGF in HKBMM treated with GO-Y030 at IC₅₀ × 2; I: The percentage of normal appearance cells in HKBMM treated with GO-Y030 at IC₅₀ × 2; J: The percentage of positive cells for N-Cad in HKBMM treated with GO-Y030 at IC₅₀ × 2; K: The percentage of positive cells for NF-Kb in HKBMM treated with GO-Y030 at IC₅₀ × 2; L: The percentage of positive cells for HGF in HKBMM treated with GO-Y030 at IC₅₀ × 2.

Figure 6

Apoptosis induction in meningioma cell lines with GO-Y030 in vitro. A: Cleaved Caspase 3 in the control of IOMM-Lee; B: Cleaved Caspase 3 induction of IOMM-Lee treated with GO-Y030 at twice concentration of the 50% inhibitory concentration (IC₅₀ × 2); C: The percentage of Cleaved Caspase 3 positive cells in IOMM-Lee treated with GO-Y030 at IC₅₀ × 2; D: Cleaved Caspase 3 in the control of HKBMM; E: Cleaved Caspase 3 induction of HKBMM treated with GO-Y030 at IC₅₀ × 2; F: The percentage of Cleaved Caspase 3 positive cells in HKBMM treated with GO-Y030 at IC₅₀ × 2.

Figure 7

Inhibition of molecular targets by GO-Y030 in vivo. A: HE stains of the control group treated with DMSO alone. The inset indicates a closer magnified view; B: HE stains of IOMM-Lee treated with GO-Y030. The inset indicates a more detailed view. Pyknotic cell nuclei are observed; C: Immunohistochemistry (IHC) of N-Cadherin (N-Cad) in the control group; D: IHC of N-Cad in IOMM-Lee treated with GO-Y030; E: IHC of nuclear factor kappa-B p65 (NF-kB) in the control; F: IHC of the NF-kB of IOMM-Lee treated with GO-Y030; G: IHC of the hepatocellular growth factor (HGF) in the control group; H: IHC of HGF in IOMM-Lee treated with GO-Y030. The red dashed line distinguishes between the cells with intact tumor nuclei that test positive for each molecule, and the cells with pyknotic nuclei that test negative affected with GO-Y030 peripherally from vessels.