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. 2024 Jan 10;15(2):310–313. doi: 10.1021/acsmedchemlett.3c00499

Enhanced Inhibition of Cancer Cell Migration by a Planar Catechin Analog

Hiromu Ito †,*, Yoshimi Shoji †,‡, Ken-ichiro Matsumoto ‡, Kiyoshi Fukuhara §,*, Ikuo Nakanishi †,*
PMCID: PMC10860178  PMID: 38352823

Abstract

graphic file with name ml3c00499_0003.jpg

Cancer cell migration is related to malignancy and patient prognosis. We previously reported that intracellular reactive oxygen species (ROS) promoted cancer cellular migration and invasion and that an antioxidant enzyme could help to attenuate the malignancy. Catechin is known as an antioxidant, and we have developed a catechin analog, planar catechin, which showed an antioxidant activity significantly stronger than that of the parent (+)-catechin. In this study, we examined the effects of the planar catechin on the migration of gastric normal and cancer cells. A scratched assay showed that the planar catechin suppressed the cellular migration rates in both normal and cancer cells, while the prevention levels in cancer cells were remarkable compared to the normal cells. These results suggest that the planar catechin with the enhanced antioxidant activity effectively scavenged the ROS overexpressed in the cancer cells and inhibited cancer cellular activities, including migration.

Keywords: Planar catechin, Gastric cancer cells, Cell migration

Cancer cellular migration and invasion are related to the metastasis and subsequent tumor formation.1,2 Therefore, the migration of cancer cells is associated with patient prognosis. To activate the ability of migration and invasion in cancer cells, reactive oxygen species (ROS), which are mainly produced in mitochondria, are reported to play an important role.3,4 ROS can activate nuclear factor-kappa B (NF-κB), which is a transcription factor, plays a pivotal role in inflammation, and is related to cancer cellular migration through the induction of matrix metalloproteinase-9 expression.5−8 On the other hand, overexpression of manganese superoxide dismutase (MnSOD), a superoxide scavenging enzyme localized in mitochondria, was reported to suppress cancer cellular migration and invasion.9 Thus, intracellular ROS scavenging by a powerful antioxidant may contribute to the inhibition of cell migration in cancer cells.

Catechin is known as an antioxidant and has some physiological effects, such as antiatherogenic effects, abdominal fat reduction, and so on.10,11 We have developed a novel catechin analog, planar catechin, which shows a 10-fold stronger scavenging capacity than the parent (+)-catechin against 2,2-diphenyl-1-picrylhydrazyl radicals solubilized in water by β-cyclodextrin in phosphate buffer (0.1 M, pH 7.4) at 298 K (Figure 1).12,13 Furthermore, we recently reported that the planar catechin showed cancer cell dominant cytotoxicity through the decrease of mitochondrial membrane potential.14 Hence, the planar catechin may also inhibit cancer cellular migration and could be a promising agent for improvement of cancer patient prognosis. We report herein the inhibitory effects of the planar catechin on the cell migration in comparison with those of (+)-catechin using a rat normal gastric cell line, RGM1, and its chemically mutated cell line, RGK1.

Figure 1.

Figure 1

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Chemical structures of (+)-catechin and planar catechin.

ROS produced in cells are related to the cell migration, and thus, a treatment with antioxidants, such as N-acetylcysteine and vitamin C, could inhibit cancer cellular migration.15−17 In this study, we examined the effects of the planar catechin, which showed a higher ROS-scavenging ability than the parent (+)-catechin, on cell migration of gastric normal and cancer cells. As shown in Figure 2a,b, the scratched areas in both RGM1 and RGK1 control samples were healed in 12 h after the assay started and those with (+)-catechin treatment showed almost the same results. However, a treatment with the planar catechin suppressed the healing, and the scratched areas were left after 12 h. Interestingly, the remarkable inhibition of the healing was observed in RGK1 cancer cells compared to RGM1 normal cells after treatment with the planar catechin (Figure 2c,d), indicating that the planar catechin predominantly suppressed the cancer cell migration. Cell migration may be related to cell proliferation. In cancer cells, ROS production is elevated and the high levels of ROS induce cell proliferation.18,19 Therefore, administration of antioxidants would enable scavenging of ROS overgenerated in cancer cells and subsequent prevention of proliferation. In fact, we have reported that a red dye derived from Monascus purpureus had high antioxidant ability and inhibited cancer cell proliferation by decreasing mitochondrial ROS.20 In addition, water-containing nanobubbled hydrogen shows superior ROS scavenging ability, and we have clarified that the nanobubbled hydrogen can inhibit cancer cell growth in vitro and tumor growth in vivo.21,22 Thus, it is suggested that the suppression of cancer cell migration in this study was induced by the strong antioxidant capacity of the planar catechin. On the other hand, several antioxidants are reported to promote migration and proliferation of skin cells and fibroblasts in vitro and in vivo.23 Moreover, some antioxidant enzymes are related to wound healing in genetically modified mice, and the induction of a cyclin-dependent kinase inhibitor is lower in SOD1-deficient mice than in wild-type mice.24 The types of antioxidants, the parts of the tissue, and genetic backgrounds may also be associated with the wound-healing process.

Figure 2.

Figure 2

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Observation and measurement of cell migration distances after treatment of (+)-catechin or the planar catechin for 0, 6, and 12 h. Representative images of migration assay of (a) RGM1 and (b) RGK1. Scale bar: 200 μm. Results of the distances between the scratched areas in (c) RGM1 and (d) RGK1. Statistical significance was tested by Tukey HSD. n = 5, mean ± SD, **p < 0.01 vs other samples at the same incubation time.

There are some chemical compounds that induce the expression of antioxidant enzyme to exert ROS scavenging ability. Nakao et al. reported that oral intake of hydrogen-rich water for 8 weeks increased SOD levels.25 Sulforaphane, which is rich in broccoli sprouts, shows an antioxidant activity through the activation of the Nrf2-Keap1 system and subsequent induction of antioxidant enzyme, such as hemeoxygenase-1.26,27 Epigallocatechin gallate, which is one of the catechin species and abundant in green tea, is also reported to activate Nrf2 via inactivating Keap1.28 Furthermore, reactive antioxidants could be pro-oxidants and new reactants with other biomolecules, because antioxidants are easily oxidized, and may be a possible inducer of Nrf2 activation.29,30 Thus, planar catechin might cause the prevention of cellular migration through the activation of antioxidant signaling pathways such as Nrf2-Keap1.

In conclusion, the catechin analog, planar catechin, which has much higher antioxidant ability than the parent (+)-catechin, showed outstanding inhibition effects on cell migration, especially in RGK1 cancer cells. We suggest that the powerful antioxidant ability of the planar catechin scavenged the ROS overexpressed in the cancer cells and resulted in the subsequent attenuation of cancer cellular activities, leading to migration prevention. These results indicate that the planar catechin could be a promising agent for attenuation of cancer cellular malignancy and could lead to improved prognosis for patients with cancer. However, the behavior of the planar catechin, including the process of uptake and metabolism in cells, is still unclear, and clarification of the detailed mechanism on the suppression of cell migration by the planar catechin is currently being pursued.

Glossary

Abbreviations

ROS

reactive oxygen species

NF-κB

nuclear factor-kappa B

SOD

superoxide dismutase

Nrf2

nuclear factor erythroid 2-related factor 2

Keap1

Kelch like ECH associated protein 1

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.3c00499.

  • Detailed description of experimental methods (PDF)

The authors declare no competing financial interest.

Supplementary Material

ml3c00499_si_001.pdf (231.8KB, pdf)

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Associated Data

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Supplementary Materials

ml3c00499_si_001.pdf (231.8KB, pdf)

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