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. 2023 Oct 3;14(10):1478–1481. doi: 10.1021/acsmedchemlett.3c00328

Anti-cancer Effect of a Planar Catechin Analog through the Decrease in Mitochondrial Membrane Potential

Hiromu Ito †,*, Yoshimi Shoji †,‡, Ken-ichiro Matsumoto ‡, Kiyoshi Fukuhara §,*, Ikuo Nakanishi †,*
PMCID: PMC10577690  PMID: 37849552

Abstract

graphic file with name ml3c00328_0004.jpg

Catechin is one of the best-known antioxidants and is reported to have some favorable physiological activities, including anti-cancer effects. We previously synthesized a catechin analog, planar catechin, which showed a 10-fold larger radical scavenging activity than (+)-catechin. However, the physiological effects of the planar catechin have remained unclear. In this study, we examined cytotoxicity and mitochondrial membrane potential after planar catechin treatment using a rat normal gastric mucosal cell line, RGM1, and its chemically induced cancer-like cell line, RGK1. Interestingly, the planar catechin showed remarkable cytotoxicity compared to (+)-catechin, with cancer cell specificity. Furthermore, the decrease in the mitochondrial membrane potential of cancer cells was observed at specific concentrations of the planar catechin. These results indicate that the planar catechin, possessing higher antioxidant activity, induces its anti-cancer effect through a decrease in the mitochondrial membrane potential and thus can be a promising agent for cancer treatment.

Keywords: planar catechin, (+)-catechin, mitochondria, anti-cancer effect

Redox imbalance derived from excess generation of reactive oxygen species (ROS) induces oxidative stress in the body, leading to many kinds of diseases, such as cardiovascular disease, neurodegenerative disease, and carcinogenesis.1 The ingestion of antioxidants is one of the most effective ways to eliminate the unwanted ROS and recover the redox balance. Recently, many types of antioxidants have been discovered and developed as supplements. Resveratrol is a polyphenol compound that is abundant in red wine and reported to suppress obesity and extend the lifespan in high-calorie-fed mice.2 Further, resveratrol is also reported to improve cardiovascular disease in animal models and show anti-cancer effects by nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway activation.3,4 Ascorbic acid, which is also known as vitamin C, also has antioxidant properties to scavenge ROS efficiently and is reported to improve the reproductive ability of superoxide dismutase 1-knockout mice.5,6 Moreover, not only low-molecular-weight compounds but also functional polymers possessing antioxidant ability have been developed to ameliorate the redox balance and cure diseases such as colitis and cancer.7,8 In addition, catechin, which is classified as a flavanol of the flavonoid family of polyphenols and rich in green tea, is also reported to have antioxidant and anti-cancer effects.9 However, regular green tea consumption does not reduce the risk of death with cancer and heart disease, although Japanese people often drink green tea. There are some case reports studying the effect of catechin compounds in green tea on cancer therapy, but no clear efficacy has been shown, unlike in cell experiments.10 Furthermore, bioavailability of catechin compounds in green tea is remarkably low in the human body, and less than 5% of the orally given dose of tea catechins reaches systemic circulation in rats.10 Therefore, development of more effective antioxidants is needed to prevent oxidative stress-related diseases including cancer and extend healthy life expectancy.

We have synthesized a catechin analog, planar catechin, which has stronger antioxidant capacity than (+)-catechin (see Figure 1 for structures).11 The planar catechin showed a 10-fold larger second-order-rate constant compared to (+)-catechin for the reaction with 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•) solubilized in water by β-cyclodextrin in a phosphate buffer (0.1 M, pH 7.4) at 298 K.12 This result indicates that the planar catechin has a 10-fold higher antioxidant activity than (+)-catechin. In addition, the planar catechin showed a more remarkable radioprotective activity and suppressed apoptotic cell death of rat thymocytes induced by X-ray irradiation compared to (+)-catechin.12 However, the effect of planar catechin on cancer cells has not been investigated. We report herein the effects of the planar catechin with strong antioxidant capacity on cancer cells using a rat normal mucosal cell line, RGM1, and its cancer-like mutant cell line, RGK1.

Figure 1.

Figure 1

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

To achieve complete remission for cancer, many kinds of anti-cancer drugs, such as doxorubicin, cisplatin, and irinotecan, have been developed. Recently, new types of anti-cancer medicines based on inhibition of immune checkpoints have been approved and are being used in the clinic.13 However, some of anti-cancer drugs cause severe side effects to normal tissues, and it is still difficult to cure most malignant solid tumors completely. Antioxidants, such as flavonoid compounds, are thought to be promising agents for cancer treatment, because cancer cells overproduce ROS to activate many kinds of signal transduction, which are associated with proliferation and metastasis.14−16 Catechin is one of flavonoid compounds and is reported to have strong antioxidant ability and anti-tumor effects.9 The planar catechin, which we previously developed, has been reported to have a 10-fold stronger antioxidant capacity compared to (+)-catechin and shows outstanding cytotoxicity compared to the normal (+)-catechin, as can be seen in Figure 2. Notably, the cytotoxic effect of the planar catechin tends to be cancer cell dominant. These results suggest that the planar catechin may influence mitochondrial homeostasis, especially in RGK1 cancer cells, because mitochondria are one of the main organelles to generate ROS and the ROS levels in cancer cells tend to be elevated.17 We actually demonstrated cancer-cell-specific induction of mitochondrial dysfunction and decrease in the membrane potential by the planar catechin, as shown in Figure 3b. Some antioxidants are reported to suppress the growth of tumor cells, and we also reported that monascus purpureus, which is a red dye derived from yeast rice, induced cancer cellular apoptosis through scavenging mitochondrial ROS.18 The removal of mitochondrial ROS by monascus purpureus decreased the expression of acid ceramidase, which catalyzes the hydrolysis of ceramides to form sphingosine, leading to cellular proliferation. Thangavel et al. also reported that a nanoparticle-loading antioxidant inhibited acid ceramidase and the accumulation of ceramides in cancer cells promoted apoptotic cell death.19 In addition, mitochondrial ROS activate signal-related proteins, such as nuclear factor-kappa B (NF-κB) and tumor necrosis factor alpha (TNF-α), which are important for the survival of cancer cells.20,21 In contrast, the generation of ROS and activation of the signaling pathway in normal cells are not activated compared to those in cancer cells. Antioxidants have the possibility to alleviate the activation of the transcription factors and cytokines in cancer cells, and these differences between normal and cancer cells may be related to the cytotoxic selectivity of the planar catechin.

Figure 2.

Figure 2

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Cell viability after (+)-catechin or the planar catechin treatment for 24 h, calculated by the water-soluble tetrazolium colorimetric assay. Statistical significance was tested by Tukey HSD. n = 6, mean ± SD, **p < 0.01.

Figure 3.

Figure 3

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Mitochondrial membrane potential after treatment with (+)-catechin or the planar catechin, monitored using MitoTracker Red CMXRos. Representative images and bar graphs of relative fluorescence intensity in RGM1 (a) and RGK1 (b) are shown. Statistical significance was tested by Tukey HSD. n = 6, mean ± SD, *p < 0.05, **p < 0.01.

As mentioned above, the planar catechin has a notable antioxidant capacity. However, such powerful antioxidants can act as pro-oxidants because they also have strong reactivities with other kinds of oxidants. Carotenoids, which are known as possible antioxidants, also act as pro-oxidants, especially in cancer cells, and induce apoptosis via influencing mitochondria.22 Further, other kinds of strong antioxidants, such as N-acetylcysteine, have been reported to induce a paradoxical increase in mitochondrial oxidative stress through mitochondrial dysfunction, which is associated with reductive stress.23 The planar catechin may also act as a pro-oxidant and/or reductive stress inducer and cause apoptosis via mitochondrial dysfunction in cancer cells.

In conclusion, the synthesized catechin analog, planar catechin, caused significant cell death compared to (+)-catechin, and the lethal effect was selectively induced in cancer cells at specific concentrations. A decrease in mitochondrial membrane potential in cancer cells was also observed with the planar catechin treatment. Thus, the planar catechin is likely to induce cancer cell death by targeting mitochondria. However, the mechanism for induction of cancer cell death and the relationship of the antioxidant ability of the planar catechin are still unknown. We are now further investigating these details.

Glossary

Abbreviations

ROS

reactive oxygen species

Nrf2

nuclear factor erythroid 2-related factor 2

DPPH•

2,2-diphenyl-1-picrylhydrazyl radical

NF-κB

nuclear factor-kappa B

TNF-α

tumor necrosis factor alpha

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.3c00328.

  • Detailed description of experimental methods (PDF)

The authors declare no competing financial interest.

Supplementary Material

ml3c00328_si_001.pdf (292.9KB, pdf)

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Supplementary Materials

ml3c00328_si_001.pdf (292.9KB, pdf)

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