The roles of traditional Chinese herbal medications in regulating mitochondrial activity to reverse cancer

Lichao Sun, Guihua Tian, Hongcai Shang*

REVIEW

The roles of traditional Chinese herbal medications in regulating mitochondrial activity to reverse cancer

Lichao Sun1,2*, Guihua Tian1, Hongcai Shang1*

1Key Laboratory of Chinese Internal Medicine of the Ministry of Education, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China;2State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China.

Cancer was gradually regarded as a metabolic disease, which might be linked to impairment of mitochondrial function. There are really some essential differences between the mitochondria of normal and cancer cells, which might become promising target for cancer chemotherapy. According to western pharmacology, a known target was needed for drug development. Unfortunately, the number of therapeutic agents relating to the mitochondrion are severely limited because of lacking of knowledge about mitochondrial biology. Unlike the “Western Medicine”, some traditional Chinese herbal medicine (TCHM) might be prone to targeting mitochondria despite the lack of precise molecular mechanisms. If it is the case, we might be able to screen and identify active anti-cancer drugs from traditional Chinese therapeutics by using mitochondrial functional assay. In this review, we would give an overview of the effect of TCHM on the mitochondrion, and the challenges and breakthroughs remaining in cancer treatment.

Traditional Chinese herbal medicine, Mitochondria, Metabolism, Cancer, Therapy

Background

Cancer is among the leading causes of death worldwide, and the number of new cases continues to increase [1]. Despite recent advances in therapeutic strategies, cancer cells would develop resistance to chemotherapies and radiotherapy, making the identification of new therapies essential to improve the survival rates of cancer patients. The mitochondrion was the major energy source for cells, and was also implicated in the regulation of programmed cell death, reactive oxygen species (ROS) generation, and calcium homeostasis [2, 3]. Recent studies have indicated that mitochondrion in tumor cells are defective when compared with ones from normal cells, which would lead to metabolic reprogramming in cancer cells[4]. In the 1920s, Dr. Otto Warburg found that cancer cells preferred glycolysis rather than oxidative metabolism to meet their energy demand regardless of whether oxygen was present [5]. Further understanding the metabolic alterations of cancer cells through mitochondrial dysfunction, may identify candidate targets for the development of novel anticancer agents. Clinical data demonstrated that some traditional Chinese herbal medicine (TCHM) possessed anticancer properties by regulating the mitochondrial function [6]. Therefore, it is reasonable to assume that identification of active components from TCHM through the mitochondrial pathway would pave the way for mitochondria-targeted cancer therapy.

Metabolic features of cancer cells

Mitochondria are involved in coordinating the metabolic process, energetic production and apoptosis modulation [7]. Structure and function of mitochondria are closely related. Abnormalities in mitochondrial structures could potentially affect the function of oxidative phosphorylation (OXPHOS), and disrupt the metabolic homeostasis [9]. Cancer cells always employed the unique metabolic modification to facilitate their proliferation, invasion and metastasis. The following points are the difference between mitochondria in cancer cells and normal cells [8].

Dysfunction of OXPHOS

Physiologically, normal cells could consume oxygen by the electron transport chain (ETC) and produce 70% of adenosine triphosphate (ATP) through OXPHOS. In most solid tumor cells, a metabolic switch towards glycolysis was used to meet energy requirements, which is known as the Warburg effect [10]. Furthermore, the intermediate metabolites of glycolytic pathway are essential for the synthesis of nucleotides, lipids, amino acids and NADPH, which could meet the biosynthetic requirements of cancer cells [11].

Enhancement of ROS generation

In normal cells, mitochondria are a major source of ROS including superoxide anion, hydroxyl radical and hydrogen peroxide, which are the by-product of mitochondrial metabolism [12]. Those short-lived ROS took part in mitochondrial signal transduction in immune modulation, autophagy and differentiation [13, 14]. Unfortunately, persistent ROS stress would result in damage to DNA, protein or lipids, which would contribute to carcinogenesis. In cancer cells, high levels of ROS could induce proteases activation genome instability and mutagenesis to facilitate cancer progression [15].

Disturbance of cholesterol metabolism

Cholesterol is not only needed for cellular functions, but also as the precursor for synthesis of steroid hormones [16]. In normal cells, mitochondria are cholesterol-poor organelles compared to other plasma membranes. Cancer cells would reprogram the cholesterol metabolism to support uncontrolled cell growth by enhancing cholesterol loading and changing membrane dynamics in mitochondria [17, 18]. Cholesterol-enriched mitochondria may partially stimulate aerobic glycolysis by hypoxia inducible factor-1α (HIF1α) stabilization, develop chemotherapy resistance and protect cancer cells from mitochondrial-mediated apoptosis [19, 20].

Targeting mitochondrial metabolism treatment

Since a great number of solid tumor derived from the mitochondria dysfunction, we boldly speculate that targeting mitochondrial energy metabolism could be effective in overcoming cancer. Increasing evidences demonstrated that some TCHM including Qi-invigorating, Activating Blood Circulation to Dissipate Blood Stasis andYang-invigorating possessed potent anti-cancer activity by targeting the mitochondrial energetic function. Then, we could identify mitochondrially active compounds from TCHM by using mitochondrial functional assay to eliminate cancer.

Qi-invigorating therapy

According to traditional Chinese medicine (TCM) principles, Qi refers to the basic motive force that constitutes the body and maintains human life activities [21]. The mitochondria is the major site of ATP production, which is the core of all life’s activities. It is reasonable that Qi and bioenergy are closely related. Studies have demonstrated that Qi-invigorating Chinese medicine includes Renshen (), Huangqi ()and Baizhu () exerted the anti-tumor activity by affecting mitochondrial ROS-related signaling pathways. Ginsenosides are a class of pharmacologically active components extracted from the Renshen. Among them, Ginsenoside Rh2 (GRh2) has been identified as an anti-tumor agent. Ge et al found that GRh2 could lead to H1299 cell apoptosis by inducing ROS production [22]. GRh2 could also cause mitochondrial damages and mediate ROS-induced mitochondria-dependent apoptosis in hepatocellular carcinoma cell line HepG2 and human leukaemia Jurkat cells [23, 24]. Astragalus polysaccharides (APS), one of the bioactive components extracted from Huangqi (), could induce the mitochondria-mediated apoptosis and inhibit the mammalian target of rapamycin (mTOR) signaling pathway in lung cancer cell H1299 [25]. It has been reported that the release of cytochrome c from the inner mitochondrial membrane and its permeabilization could trigger the apoptosis [26]. APS4, a novel cold-water-soluble polysaccharide from Huangqi, could lead to mitochondria-dependent apoptosis by promoting cytochrome c release and the collapse of mitochondrial membrane potential [27].

B-cell lymphoma-2 (Bcl-2, an apoptosis inhibitor) and B-cell lymphoma-2-associated X protein (Bax, an apoptosis promoter) played key roles in mitochondrial related apoptosis pathway[28]. Atractylenolide I (ATR-I) from Baizhu () also exerted anticancer properties on several types of cancer cell lines. ATR-I suppressed bladder cancer cell growth via Bax activation and triggered the release of cytochrome c from the mitochondria into cytosol[29]. Incolon cancer,Atractylenolide I (AT-I) inhibited pro-survival Bcl-2 in HT-29 cells [30]. Similarly, Atractylenolide Ⅲ (ATL-Ⅲ) also lead to apoptosis by inducing Bax translocation in human lung carcinoma A549 cell [31].

Activating Blood Circulation to Dissipate Blood Stasis therapy

Activating Blood Circulation to Dissipate Blood Stasis (ABCDBS) TCM has anti-inflammation and anti-tumor activities by regulating the mitochondrial function.An active compound extracting from Chuanxiong (), Tetramethylpyrazine (TMPZ) could inhibit cell viability and induce mitochondrial-apoptosis by stimulating AMP-activated protein kinase (AMPK) in gastric cancer and liver cancer cells [32-34]. Salvianic acid A (SAA) is another kind of ABCDBS renowned TCM. Wang et al developed a novel conjugate of SAA and TMPZ, named DT-010, could inhibit the growth of breast cancer cell lines by suppressing mitochondrial complex Ⅱ [35].

Chronic inflammation have been recognized as important factors for carcinogenesis, which could suppress mitochondrial respiratory chain[36]. Bissell MJ et al described that chronic inflammation could induce acute mitochondrial failure by enhancing the TGF-β expression in cancer tissues [37]. Hydroxysafflor yellow A (HSYA), extracting from the safflower, could significantly reverse the effects of chronic inflammation induced by Lipopolysaccharide (LPS) on A549 and H1299 cells [38]. Meanwhile, HSYA effectively protected the liver cells from alcohol-induced injury by TGF-β inhibition[39]. Mitochondria dynamics is closely associated with cancer progression and apoptosis [41]. Tanshinone ⅡA (Tan ⅡA), which is isolated from the roots of Danshen (), also exhibited significantly antitumor activity by regulating mitochondria homeostasis. It could promote mitochondrial fission by activating JNK-Mff signaling pathways to inhibit the proliferation of colorectal cancer cell SW837 [42]. Moreover, Tan ⅡA could increase IL-2-mediated cell death in SW480 colorectal cancer cells by promoting mitochondrial fission via activating the Mst1-Hippo pathway [43].

Yang-invigorating therapy

Some Yang-tonic traditional Chinese herbs have been found to involve in regulating mitochondrial function by stimulating electron transport and producing antioxidant defense components[44]. Fuzi(), which is the processed lateral roots of Aconitum carmichaeli Debx., is well known for its anti-inflammatory effects and acute toxicity. Benzoylaconine (BAC), a representative alkaloids from Fuzi, couldincrease mitochondrial mass and induce mitochondrial biogenesis in HepG2 cells through activating AMPK signal pathway[45]. But further study was needed to study the effect of Fuzi derivates on cancer cells. The extracts of Buguzhi () could disrupt the ETC and induce apoptosis in the murine TA3/Ha mammary adenocarcinoma cell line [46]. In addition, Buguzhi could inhibit colorectal or gastric cancer cell growth and induce mitochondrial-mediated apoptosis [47, 48]. Increase in mitochondrial calcium induces the permeability of the outer mitochondrial membrane, mitochondrial dysfunction and apoptosis [49]. Rougui (),a widely used food spice, has shown the anti-tumor activity by affecting mitochondrial calcium signaling. Aqueous cinnamon extract (ACE-c) could leading to apoptosis in human cervical cancer cell line (SiHa) through increasing intracellular calcium flux and disruption of mitochondrial membrane potential [50]. It could be used as a potential chemopreventive medicine. Chlorogenic acid (CGA) from Duzhong () exerted antitumor effect via mitochondrial- mediated apoptosis in cancer [51]. For example, CGA could directly interact with PKC, which would be translocated from the cytosol to the plasma membrane, and induced apoptosis in human breast cancer MDAMB-231 and MCF-7 cells. Cancer stem cell (CSC) was responsible for the origin of cancers, tumor recurrence, and drug resistance [52, 53]. Interestingly, CGA could lead to apoptosis of cancer stem like cells from lung cancer cells A549 by down-regulation of Bcl2 and up-regulation Bax andCaspase-3 [54]. In liver cancer, CGA, as a novel chemosensitizers, couldsensitize to the effects of 5-fluorouracil on HepG2 and Hep3B by activating mitochondria-dependent apoptosis pathway [55].

Future

Altered cellular metabolism is one of the hallmarks of cancer[56]. The best-known metabolic abnormality in many types of cancer is Warburg effect. Mitochondria is a specialized organelle for the production of the energy substance ATP by OXPHOS, calcium flux and apoptosis. Mitochondrial dysfunctionhas been associated with carcinogenesis[57]. At the molecular level, abnormal mitochondrion displayed the following changes including loss of mitochondrial membrane potential, alterations of electron transport chain and transportation of metabolites. In turn, these changes could led to cell metabolism disorders and boost excessive free radical production. It is possible that normalization of mitochondrial function might suppress tumorigenesis[58]. Therefore, mitochondria have emerged as attractive candidate cancer targets.

TCHM have a long history of clinical testing and reliable therapeutic efficacy. It has been regarded as an important source of development of new drugs for human diseases. A rapidly growing number of literatures proposed that TCHM could directly or indirectly use mitochondria as the target to regulate mitochondrial functions to perform their pharmaceutical efficacy in coronary artery disease, diabetes and neurodegenerative diseases[59, 60] For cancer treatment, the extracts of TCHM could sensitize the cancer cells to chemotherapy/radiotherapy and prevent cancer recurrence and metastasis, and prolong cancer patients’ survival[61, 62]. Remarkably, some TCHM might regulate the function of mitochondria via enhancement of mitochondrial oxidative phosphorylation, or modulation of mitochondrial-mediated apoptosis, and reduction of excess free radicals, although lacking of precise molecular mechanisms.Therefore, TCHM might be the valuable pool for identification of the candidate mitochondria-targeting medicine for cancer therapy.

In the future, it is necessary to use mitochondrial functional assay to screen and identify novel candidate modulators to treat cancer. Furthermore, it might reveal previously unrecognized mitochondrial pathways which would play key roles in carcinogenesis.

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Cancer was considered as a metabolic disease because of mitochondrial dysfunction. Some mitochondrion-targeting traditional Chinese herbal medicine (TCHM) displayed some advantages in cancer therapy. In this review, we would give an overview of the effect of TCHM on the mitochondrion, the challenges and breakthroughs remaining in cancer treatment.

:Sun LC, Tian GH, Shang HC. The roles of traditional Chinese herbal medications in regulating mitochondrial activity to reverse and prevent cancer. TMR Modern Herbal Medicine 2020, 3(2): 121-127.

Executive Editor: Chaoyong Wu

Submitted: 1 April 2020,

20 April 2020,

*Correspondence to: Hongcai Shang, Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, No.5 Haiyuncang Hutong, Dongcheng District, Beijing 100700, China. Email: shanghongcai@126.com

Lichao Sun, Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, No.5 Haiyuncang Hutong, Dongcheng District, Beijing 100700, China. Email: Prof_sunlichao@163.com

Abbreviations: ROS, reactive oxygen species; TCHM, traditional Chinese herbal medicine; OXPHOS, oxidative phosphorylation; ETC, electron transport chain; ATR-I, Atractylenolide I; ATL-Ⅲ, Atractylenolide Ⅲ; TMPZ, Tetramethylpyrazine; AMPK, AMP-activated protein kinase; HSYA, Hydroxysafflor yellow A; LPS, Lipopolysaccharide; Tan ⅡA, Tanshinone ⅡA; CGA, Chlorogenic acid; CSC, Cancer stem cell; Bax, B-cell lymphoma-2-associated X protein; GRh2, Ginsenoside Rh2; APS, Astragalus polysaccharides.

Funding: This work was supported by the National Natural Science Foundation of China (No. 81773170), BeijingNovaProgram(No. Z1511000003150121), Beijing Talents Fund (No. 2015000021223ZK23).

Competing interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Online: 25 April 2020.