Tanshinone IIA (Tan IIA) is a pharmacologically lipophilic active constituent isolated from the roots and rhizomes of the Chinese medicinal herb Salvia miltiorrhiza Bunge (Danshen). Tan IIA is currently used in China and other neighboring countries to treat patients with cardiovascular system, diabetes, apoplexy, arthritis, sepsis, and other diseases. Recently, it was reported that tan IIA could have a wide range of antitumor effects on several human tumor cell lines, but the research of the mechanism of tan IIA is relatively scattered in cancer. This review aimed to summarize the recent advances in the anticancer effects of tan IIA and to provide a novel perspective on clinical use of tan IIA.

Introduction

Salviae miltiorrhiza (Danshen) is the dried root and rhizome of Salvia miltiorrhiza Bge (Lamiaceae), which is a traditional Chinese medicine herb (Figure 1) (Tseng et al., 2014). It is mainly distributed in Anhui, Shanxi, Hebei, Sichuan, Shandong, Jiangsu, and other provinces in China and considered to have the action of relieving pain, activating blood circulation and removing blood stasis, clearing the heart and removing annoyance, cooling blood, and eliminating carbuncle, according to the mechanism of traditional Chinese medicine (TCM) (Li et al., 2016a; Zhou et al., 2019). There are two main active ingredients in S. miltiorrhiza. One is the hydrophilic component, which belongs to water-soluble substances, such as tanshinol, and the other is the lipophilic component, which belongs to fat soluble substances, such as tanshinone I and tan IIA (Kwak et al., 2008; Shang et al., 2012; Lin et al., 2019).


 

Tan IIA (C₁₉H₁₈O₃, 14,16-epoxy-20-nor-5(10),6,8,13,15-abietapentaene-11,12- dione) (Wei et al., 2012), a natural diterpene quinone in S. miltiorrhiza, possesses miscellaneous biological activities such as anti-inflammatory (Dong et al., 2009; Li et al., 2015a; Fan et al., 2016), antiviral (Xiao et al., 2013; Zhang et al., 2014a), antioxidant (Gong et al., 2019), neuron-protective (Xia et al., 2005; Weng et al., 2018), antiatherosclerotic (Chang et al., 2014a; Tan et al., 2019), antiallergic (Li et al., 2018a; Heo and Im, 2019), anticonvulsant (Olivia et al., 2013), antifatigue (Lin et al., 2017), anti-Alzheimer’s disease (Jiang et al., 2014; Li et al., 2015b), and antiangiogenic activities (Fan et al., 2011), reducing organ damage (Ma et al., 2018a), and protection from angina pectoris and myocardial infarction (Lv et al., 2018) (its structure is shown in Figure 1). Newly, it was said that tan IIA could have a wide range of antitumor effects in multiple human tumor cell lines by inhibiting tumor growth, inducing apoptosis, regulating cell cycle, regulating signaling pathways, and reversing the multidrug resistance in various human tumor cells (Kim et al., 2015). However, because the mechanism of tan IIA cell is relatively scattered in cancer, this paper provides the research progress of the antitumor effect of tan IIA on leukemia, lung cancer, hepatocellular carcinoma, gastric carcinoma, colorectal cancer, glioma, osteosarcoma, cervical cancer, ovarian cancer, breast cancer, and prostate cancer, and its antitumor mechanism was also discussed.

Antitumor Effects

Tan IIA could exhibit antitumor activity in many cancer cells such as leukemia, lung cancer, hepatocellular carcinoma, gastric carcinoma, colorectal cancer, glioma, osteosarcoma, cervical cancer, ovarian cancer, breast cancer, and prostate cancer. Tan IIA could induce autophagy and apoptosis and inhibit cell growth and migration, by activating AMPK and inhibiting PI3K/Akt/mTOR signaling pathway, and so on.

Leukemia

Leukemia, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and acute promyelocytic leukemia (APL), is one of the blood or bone marrow cancers. Some viruses, petrochemical products, ionizing radiation, and alkylating chemotherapy drugs are considered as major reasons of leukemia (Liu et al., 2012a). Around 100 million children and adults worldwide suffer from some forms of leukemia every year. At present, the treatment of leukemia remains a top research priority. In recent years, TCM has attracted wide attention as a clinical alternative to the treatment of leukemia because of its anti-inflammatory, antivirus, antioxidation, antitumor, apoptosis inducing effect (Boon and Wong, 2004). Among them, Tan IIA played an important role.

CML is a myeloproliferative disease. The translocation of chromosomes 9 and 22 leads to the clonal inflation of transformed hemopoietic stem cells, which may lead to resistance in tumor treatment (Yun et al., 2013a). Yun, et al. observed that tan IIA induced mitochondria dependent apoptosis through excitation of JNK in KBM 5 leukemia cells (Yun et al., 2013a). Tan IIA could raise sub-G1 apoptotic portion, activate Caspases 9 and 3, release cytochrome c from mitochondria into cytoplasm, and downregulate Survivin, Bcl-2, Bcl-xL, and c-IAP2 (Yun et al., 2013a). Then, they also discovered that tan IIA could induce autophagy via AMPK and ERK and restraint of mTOR and p70 S6K (Yun et al., 2013b).

AML is characterized by unlimited proliferation of myeloid cells (Liu et al., 2012a), with five-year mortality rate of more than 70% (Zhang et al., 2019). Therefore, we need to find more effective therapeutic strategies to treat AML. Zhang et al. revealed that tan IIA may induce apoptosis and autophagy in U937 cells via inhibiting PI3K/Akt/mTOR signaling pathway (Zhang et al., 2019). Tan IIA induced apoptosis in U937 cells via upregulating the levels of active Caspase 3 and Bax and downregulating Bcl-2. In addition, tan IIA inhibited the capacity of migration and invasion in U937 cells. Liu et al. discovered that tan IIA activated P × R (Pregnane × receptor), which inhibited nuclear factor-κB (NF-κB) activity, leading to significantly downregulating the expression of CCL2 by about ten times (Liu et al., 2012a).

APL is a seldom seen disease accounting for about 10% of AML. Zhang et al. indicated that C/EBPβ and CHOP participate in tan IIA induced variation and apoptosis of APL cells (Zhang et al., 2010). Tan IIA may upregulate C/EBPβ and CHOP; the C/EBPβ was very important (Zhang et al., 2010). Liu et al. suggested that tan IIA could induce apoptosis by excitation of Caspase 3, downregulation and upregulation of Bcl-2 and Bax, respectively, and the disruption of mitochondrial membrane potential (Liu et al., 2006). Moreover, the treatment by tan IIA may weaken adhesion and invasion of NB4 cells through the extracellular matrix (ECM). Yoon et al. demonstrated that induced apoptosis by tan IIA was accompanied by the PARP specific proteolytic cleavage and Caspase 3 activation (Yoon et al., 2000).

Liu et al. indicated that tan IIA has available antiproliferation effect on THP-1 cells by apoptosis; it is basically related to the destruction of Δψm (the mitochondrial membrane potential), activation of Caspase 3, and downregulation and upregulation of Survivin and Bax, respectively (Liu et al., 2009).

Guo et al. demonstrated that nutlin-3 and tan IIA meaningfully potentiated the apoptotic effect of imatinib by downregulating AKT/mTOR pathway (Guo et al., 2017). Next year, they showed that the association of nutlin-3 and tan IIA may synergistically induce apoptosis, cytotoxicity, cell cycle arrest, and autophagy; thus the antileukemia effect was through effective activation of p53, inhibition of the AKT/mTOR pathway, and activation of the RAF/MEK pathway (Guo et al., 2018) (its anticancer pathway is shown in Figure 2).

Recently, TCM has played more and more important roles in health conservation, the prevention and treatment of diseases, and plant drug detection.

The use of TCM to prevent the occurrence and revolution of multiple malignant diseases has become an important choice for the cure of malignant disease.

There has been great effort not only to develop new drugs, but also to conclude how the consisting ingredients exhibit their activities. 

S. miltiorrhiza has been widely used in eastern countries, especially in China, to treat miscellaneous diseases for its extraordinary pharmacological actions, including free radical scavenging, anticoagulation, and vasodilatation.

Tan IIA is an effective component in the extract of S. miltiorrhiza Bunge, which has been diffusely used in TCM exercise for more than thousand years to treat diverse diseases.

It significantly induced apoptosis on a panel of cancer cells, such as leukemia, lung cancer, hepatocellular carcinoma, gastric carcinoma, colorectal cancer, glioma, osteosarcoma, cervical cancer, ovarian cancer, breast cancer, and prostate cancer.

Overall, Tan IIA has remarkable prohibitive effect on a variety of tumor cells and its possible mechanism involves regulating cell cycle, inhibiting cell diffusion, inducing apoptosis and differentiation, inhibiting tumor aggression and diversion, inhibiting angiogenesis and reversing tumor MDR, and so on.

Tan IIA, as a sort of medicine possessing multiple pharmacological actions, has the characteristics of high efficiency, low toxicity, and natural source and possessed considerable potential value clinically. The combination of tan IIA and other clinical commonly chemotherapeutic drugs could enhance the therapeutic effect of chemotherapeutic drugs, which makes tan IIA have a good application prospect in tumor therapy and adjuvant therapy and also provides a new idea for various cancer treatment.