OriJi combines Rabdosia Rubescens Extract (containing Oridonin) and a supercritical extract of Spatholobus suberectus. Studies of these herbs and their active components report powerful effects on enhancing the immune systems response to tumor growth. Ori-ji may help disrupt pathways involved in development of several types of tumors as well as modulating the immune system to achieve a healthy inflammatory response.

Rabdosia rubescens Compound: Oridonin] (dong ling cao)

Rabdosia rubescens and its extract oridonin have been shown to be able to suppress disease progress, reduce tumor burden, alleviate syndrome and prolong survival in patients.1 Oridonin and was shown to be a potent apoptosis inducer in a variety of cancer cells.2

The aerial parts of RR and other species of the same genus have been reported to have the functions of clearing ‘heat’ and ‘toxicity’, nourishing ‘yin’, removing ‘blood stasis’, and relieving swelling. RR has been used to treat stomachache, sore throat and cough. Moreover, RR and its extracts have been shown to be able to suppress disease progress, reduce tumor burden, alleviate syndrome and prolong survival in patients with gastric carcinoma, esophageal, liver and prostate cancers.3

Among the diverse activities of oridonin, its effect on the immune system and on pro-inflammatory mediators is one of the most important. Oridonin was reported to promote differentiation of cluster of differentiation (CD)-4+/CD25+ T-regulatory (Treg) cells, and to modulate the T-helper (Th)-1/Th2 balance in rat splenic lymphocytes.4

An investigation of the effect of oridonin on intracellular tumor necrosis factor (TNF)-alpha expression revealed that the compound augments endogenous pro-TNF alpha expression and its upstream protein IkB phosphorylation.5 Oridonin also blocked TNF-alpha and lipopolysaccharide-stimulated NF-kappa activity in Jurkat cells as well as in RAW264.7 murine macrophages.6

Oridonin was reported to enhance phagocytosis of apoptotic bodies by activating PI3K-, PKC-, and ERK-dependent pathways in human macrophage-like U937 cells.7

Another study demonstrated that Ras/Raf/ERK signaling pathway-dependent Ikappa-Balpha degradation, resulting in NF-kappa B activation, participates in regulation of oridonin-enhanced phagocytosis, and that one of its effector functions is to induce the synthesis of interleukin (IL)-1 beta, which partially contributes to its phagocytic activity. 8

Oridonin facilitated the phagocytic activity against apoptotic cells through TNF alpha and IL-1 beta release, thereby contributing to its anti-tumor activities. Moreover, oridonin pretreatment inhibits the release of pro-inflammatory mediators, including nitric oxide, TNF alpha, IL-1 beta, and IL-6, resulting in the inhibition of the DNA-binding activity of NF-kappa B.9 Oridonin is also reported to be a potential modulator for trinitrobenzene sulfonic acid-induced colitis and other Th1/Th17-mediated inflammatory diseases.10

Interestingly, other Isodon plants including Isodon japonicus Hara (IJ) and I. trichocarpus (IT) are also applied as home remedies for similar disorders in Japan and Korea. These reports suggest that Isodon plants should have at least one essential anti-tumor component. In the 1970s, a bitter tetracycline diterpenoid compound, oridonin, was isolated from RR, IJ, and IT separately, and was shown to be a potent apoptosis-inducer in a variety of cancer cells.  11 1

Anti-cancer effect

There is currently research being undertaken regarding the relationship between the chemical structure/modifications and the molecular mechanisms underlying its anti-cancer activity, such as suppression of tumor proliferation and induction of tumor cell death, and the cell signal transduction in anti-cancer activity of oridonin.12

Oridonin exhibited anti-proliferative activity toward all cancer cell lines tested, with an IC50 estimated by the MTT cell viability assay ranging from 5.8+/-2.3 to 11.72+/-4.8 microM. Flow cytometric analysis demonstrated that oridonin induced a G1 phase arrest in androgen receptor-positive LNCaP cells containing wt p53, while it blocked the cell cycle at G2 and M phases in androgen receptor-negative DU-145 cells with mutated p53; the arrest in M was verified by examination of cell morphology and by the increased frequency of cells with Ser-10 phosphorylated histone H3.13

Antiangiogenic activity has been identified in an aqueous EtOH extract of Rabdosia rubescens. Bioassay-guided fractionation using a novel in vitro human endothelial cell-based assay for angiogenesis afforded the diterpenoids ponicidin (1) and oridonin (2), with significant antiangiogenic activity at subcytotoxic concentrations, suggesting that these constituents may strongly contribute to the demonstrated clinical efficacy as a treatment for advanced prostate cancer.14

The antitumor activity of oridonin has been widely investigated and evidence suggests that oridonin may effectively inhibit the proliferation of multiple cancer cell types, including human breast cancer, gastric cancer, leukemia, gallbladder cancer, cervical carcinoma, and hepatocellular carcinoma. Previous studies have revealed mechanisms by which oridonin can trigger autophagy, enhance phagocytosis, arrest cell cycle progression, and promote apoptosis by modulation of relevant signaling pathways associated with the regulation of intracellular reactive oxygen species (ROS), Bcl-2/Bax, p53/p21, JNK, nuclear factor-kappa B (NF-κB), MAPK, PI3K, and fatty acid synthesis pathways.15

Oridonin regulates multi-signaling pathways related to autophagy, apoptosis, phagocytosis, and cell cycle arrest.

In a human prostate cell line, DU-145, oridonin upregulates p53 and Bax and downregulates Bcl-2 expression in a dose-dependent manner. In Hela cells, oridonin-induced autophagy is negatively regulated by Ras but positively regulated by p38 and JNK MAPKs. Additionally, in HepG2 cells, oridonin was reported to increase the expression levels of p-JNK, p-p38, p-p53, and p21 and elevate the level of cyclin B1/p-Cdc2 (Tyr15) complex, which results in G2/M cell cycle arrest and apoptosis through MAPK and p53 pathways. Oridonin also induces apoptosis via inhibiting PTK-mediated Ras-Raf-JNK and PI3K-Akt survival pathways in L929 and cervical carcinoma Hela cells, respectively. Moreover, oridonin can trigger apoptosis through activating both classic extrinsic pathways, such as Fas/FasL and Apo2L/DR5-mediated signaling pathways, and mitochondrial-mediated intrinsic pathways in several cancer cells. In U937 cells, oridonin was reported to activate NF-κB via Ras/Raf1/ERK signaling pathway-dependent IκBα degradation and subsequently regulate oridonin-enhanced phagocytosis. In colorectal cancer cells, oridonin has been shown to increase the intracellular hydrogen peroxide level and reduce the glutathione content in a dose-dependent manner. It was also reported that oridonin induces a rapid and significant generation of ROS in L929 cells and subsequently upregulates the expression of phospho-p53 and increases expression ratio of Bax/Bcl-2. Modulations of these pathways in different cell models may explain the broad range of anticancer activities of oridonin.15 

Breast cancer

Oridonin treatment significantly inhibited the proliferation of both MDA-MB-231 and MCF7 cells in a dose and time-dependent manner. MDA-MB-231 was more sensitive to the effects of oridonin, with almost complete inhibition of cell viability observed at 20μM after 48 hours. TUNEL-positive MDA-MB-231 cells significantly increased after 20 μM oridonin treatment (40.70%) for 24 hours, which reflected the number of apoptotic cells. Apoptotis was associated with the upregulation of pro-apoptotic protein Bax and a reduction in its counterpart (Bcl-2). Oridonin also induced a significant decrease in NF-κB inhibitors, IKKα and IKKβ, as well as phospho-mTOR, and a slight downregulation in NF-κB (p65) protein expression after 24 hours. NF-κB and regulators might contribute to the reduction of Bcl-2/Bax ratio.16

Clonogenicity (colony formation or tumor growth propensity) of MCF-7 cells was significantly reduced by ponicidin or oridonin, which are two diterpenoids isolated from R. rubescens. Minimum efficacy was observed at 1.0 and 5.0 μM for oridonin. Oridonin showed a more pronounced inhibitory effect in MCF-10A than in MCF7 cells. Similarly, cell growth was inhibited by 5 μM ponicidin or oridonin after 72 hours in MCF7 and MCF10a cells. Oridonin increased cells in the G1 phase of MCF7 cells by 12.8% compared to control, whilst decreasing S and G2/M phases. Cell cycle arrest at the S to G2/M phase (47.3% to 0%), as well as apoptosis (12.4%) was evident in oridonin-treated MCF-10A cells. Both ponicidin and oridonin reduced p65 and p50 subunits of NF-κB, as well as I-κB (NF-κB activator) in MCF-10A cells, but not in MCF7 cells. NF-κB subunits may be modified or inaccessible to either oridonin or ponicidin in MCF7 cells, but await further investigation.17

Oridonin induced potent growth inhibition on human breast cancer cells MCF-7 and MDA-MB-231 in a time- and dose-dependent manner. According to the flow cytometric analysis, oridonin suppressed MCF-7 cell growth by cell-cycle arrest at the G2/M phase and caused accumulation of MDA-MB-231 cells in the Sub-G1 phase. Oridonin triggered the reduction of Bcl-2/Bax ratio, caspase-8, NF-κB (p65), IKKα, IKKβ, phospho-mTOR, and increased expression level of cleaved PARP, Fas and PPARγ in a time-dependent manner.

Oridonin inhibited the growth and induced apoptosis in breast cancer cells, which might be related to DNA damage and activation of intrinsic or extrinsic apoptotic pathways. Moreover, oridonin also inhibited tumor invasion and metastasis in vitro, possibly via decreasing the expression of MMPs and regulating the Integrin β1/FAK pathway in MDA-MB-231 cells.18

Breast cancer - TNBC

A series of new oridonin analogs (2.5 µM) were used against the human TNBC cell lines HCC1806, HCC1937, Hs578T and SUM149PT. One of the analogs, CYD-6-28, dose dependently inhibited the growth of the TNBC lines with an IC50 of approximately 1–4 µM. The IC50s of CYD-6-28 in the HCC1937 and HCC1806 cells were 2–3 µM, whilst the IC50s of oridonin in these cell lines are 15 and 40 µM, respectively. CYD-6-28 (1-4 μM) induced cell cycle G2/M phase arrest and apoptosis in HCC1806 and HCC1937 cells. CYD-6-28 decreased the phosphorylation levels of STAT3 and AKT in the HCC1806 and HCC1937 cells in a time- and dose-dependent manner. CYD-6-28 may inhibit TNBC through the induction of DR5, p21 and pERK and downregulation of Cyclin D1, FLIPL, XIAP, pSTAT3 and pAKT.19 

Breast cancer, Prostate cancer,  NSCLC, Leukemia, Glioblastoma

Oridonin has been found to effectively inhibit the proliferation of a wide variety of cancer cells including those from prostate (LNCaP, DU145, PC3), breast (MCF-7, MDA-MB231), non-small-cell lung (NSCL) (NCI-H520, NCI-H460, NCI-H1299) cancers, acute promyelocytic leukemia (NB4), and glioblastoma multiforme (U118, U138). Oridonin induced apoptosis and G0/G1 cell- cycle arrest in LNCaP prostate cancer cells. In addition, expression of p21waf1 was induced in a p53-dependent manner.

Taken together, the results indicate that oridonin inhibited the proliferation of cancer cells via apoptosis and cell-cycle arrest with p53 playing a central role in several cancer types which express the wild-type p53 gene. Oridonin may be a novel, adjunctive therapy for a large variety of malignancies.20

Colorectal cancer

Oridonin induced potent growth inhibition, cell-cycle arrest, apoptosis, senescence and colony-forming inhibition in three colorectal cancer cell lines in a dose-dependent manner in vitro. Daily i.p. injection of oridonin (6.25, 12.5 or 25 mg/kg) for 28 days significantly inhibited the growth of SW1116 s.c. xenografts in BABL/C nude mice. Oridonin possesses potent in vitro and in vivo anti-colorectal cancer activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell-cycle arrest. Therefore, oridonin may represent a novel therapeutic option in colorectal cancer treatment as it has been shown to induce apoptosis and senescence of colorectal cancer cells in vitro and in vivo.21

The increase in hydrogen peroxide and glutathione depletion account for oridonin-induced apoptosis and senescence in colorectal cancer cells, and TrxR inhibition is involved in this process. Given the importance of TrxR as a novel cancer target in colorectal cancer, oridonin would be a promising clinical candidate. The mechanism of oridonin-induced inhibition of TrxR warrants further investigation.22

Oridonin treatment upregulated the expression levels of Bim, Bax, cytosolic cytochrome c, cleaved caspase-9 and cleaved caspase-3 proteins, downregulated the expression levels of Bcl-2, procaspase-9 and procaspase-3 proteins, and meanwhile obviously activated caspase-9 and caspase-3 in a dose-dependent manner in HCT-116 and LoVo cells. The results of qRT-PCR demonstrated that oridonin treatment significantly decreased miR-32 expression, and furthermore, suppression of miR-32 expression by miR-32 inhibitors augmented oridonin-mediated inhibitory and apoptotic effects in HCT-116 and LoVo cells. Therefore, these findings suggest that oridonin maybe is a potential candidate for colorectal cancer treatment.23

Gastric cancer

After treatment with 10 μg/mL oridonin for 24 hours and 48 hours, the gastric cancer HGC-27 cells were stained with acridine orange/ethidium bromide. After treatment with oridonin for 24 hours, the effects of oridonin on expression of Apaf-1, Bcl-2, Bax, caspase-3 and cytochrome c were also analyzed using reverse-transcript polymerase chain reaction (RT-PCR) and Western blotting. Oridonin significantly inhibited the proliferation of HGC-27 cells in a dose- and time-dependent manner.

After treatment with oridonin, the cells became round, shrank, and developed small buds around the nuclear membrane while forming apoptotic bodies. Lactate dehydrogenase (LDH) release assay showed that after being treated with 1.25 μg/mL and 20 μg/mL oridonin for 24 hours, LDH release of HGC-27 caused by apoptosis increased from 22.94% ± 3.8% to 52.68% ± 2.4% (P < 0.001).

Apoptosis of HGC-27 induced by oridonin may be associated with differential expression of Apaf-1, caspase-3 and cytochrome c, which are highly dependent upon the mitochondrial pathway.24

Lymphocytic leukemia, Ehrlich Ascites tumor

Oridonin has been found to also increase lifespan of mice bearing Ehrlich ascites or P388 lymphocytic leukemia. Oridonin triggered apoptosis in more than 50% of t(8;21) leukemic cells in vitro at concentration of 2 M or higher accompanied by degradation of AE oncoprotein, and showed significant anti-leukemia efficacies with low adverse effects in vivo. These data suggest possible beneficial effects for patients witht acute myeloid leukemia (AML).2

Osteosarcoma

It has been reported that oridonin (ORI) can inhibit proliferation and induce apoptosis in various types of cancer cell lines. However, the exact mechanism for this function remains unclear. In this study, we investigated the proliferation inhibitory effect of ORI on human osteosarcoma (OS) 143B cells and dissected the possible molecular mechanism(s) underlying this effect. We demonstrated that ORI can inhibit proliferation, induce apoptosis and arrest the cell cycle in 143B cells. Using luciferase reporter assay, we found that the Wnt/β-catenin signaling was inhibited in 143B cells by ORI. Accordingly, the total protein levels and nuclear translocation of β-catenin were reduced by ORI treatment. ORI increased glycogen synthase kinase 3β (GSK3β) activity and upregulated Dickkopf-1 (Dkk-1) expression. We found that Dkk-1 overexpression or β-catenin knockdown can potentiate the proliferation inhibitory effect of ORI in 143B cells, while β-catenin overexpression attenuated this effect. Using the xenograft tumor model of human OS, we demonstrated that ORI effectively inhibited the growth of tumors. Histological examination showed that ORI inhibited cancer cell proliferation, decreased the expression of PNCA and β-catenin. Our findings suggest that ORI can inhibit 143B OS cell proliferation by downregulating Wnt/β-catenin signal transduction, which may be mediated by upregulating the Dkk-1 expression and/or enhancing the function of GSK3β. Therefore, ORI can be potentially used as an effective adjuvant agent for the clinical management of OS.25

Ovarian cancer; Anti-inflammatory

Oridonin was suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well- documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these types of compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted.26

Prostate cancer, Breast cancer, Ovarian cancer

The increased incidence of apoptosis, identified by characteristic changes in cell morphology, was seen in tumor lines treated with oridonin. Notably, at concentrations that induced apoptosis among tumor cells, oridonin failed to induce apoptosis in cultures of normal human fibroblasts. Western blot analysis was used to determine the protein expression of cancer suppressor genes, p53 (wt) and Bax, and the proto-oncogene, Bcl-2, in LNCaP cells following treatment with oridonin. Oridonin up-regulated p53 and Bax and down-regulated Bcl-2 expression in a dose-dependent manner.

Oridonin inhibits cancer cell growth in a cell-cycle specific manner and shifts the balance between pro- and anti-apoptotic proteins in favor of apoptosis. The data suggest that further studies are warranted to assess the potential of oridonin in cancer prevention and/or treatment.27

Prostate cancer

Oridonin (ORI) could inhibit the proliferation and induce apoptosis in various cancer cell lines. After ORI treatment, the proliferations of human prostate cancer (HPC) cell lines PC-3 and LNCaP were inhibited in a concentration- and time-dependent manner. ORI induced cell-cycle arrest at the G2/M phase. Autophagy occurred before the onset of apoptosis and protected cancer cells in ORI-treated HPC cells. P21 was involved in ORI-induced autophagy and apoptosis.28

Supercritical extract of Spatholobus suberectus/ Millettia reticulata (ji xue teng)

The Chinese herb Spatholobus suberectus (ji xue teng) is commonly prescribed to cancer patients. In this study, the anti-cancer effect of SS and its molecular mechanisms have been investigated. Cell growth assay showed that SS effectively inhibits tumor cell growth in a dose-dependent manner and experiments show that the efficiency of SS alone group was superior to docetaxel or to docetaxel and SS combined. SS is a potential herb for cancer treatment by inhibiting tumour growth via induction of apoptosis and arrest of the cell cycle at G2/M phase.29

Breast cancer
Aerobic glycolysis is an important feature of cancer cells. In recent years, lactate dehydrogenase A (LDH-A) is emerging as a novel therapeutic target for cancer treatment. Seeking LDH-A inhibitors from natural resources has been paid much attention for drug discovery. Spatholobus suberectus (SS) is a common herbal medicine used in China for treating blood-stasis related diseases such as cancer. This study aims to explore the potential medicinal application of SS for LDH-A inhibition on breast cancer and to determine its bioactive compounds.

Wang Z et al., (2013) found that SS manifested apoptosis-inducing, cell cycle arresting and anti-LDH-A activities in both estrogen-dependent human MCF-7 cells and estrogen-independent MDA-MB-231 cell. Oral herbal extracts (1 g/kg/d) administration attenuated tumor growth and LDH-A expression in both breast cancer xenografts. The preclinical study thus suggests that the potential medicinal application of SS for inhibiting cancer LDH-A activity and the possibility to consider its component epigallocatechin as a lead compound to develop LDH-A inhibitors.16

Breast cancer - Ki67

Recent data from neoadjuvant studies, predominantly for endocrine therapy but also for chemotherapy, indicate that a single measurement of the nuclear proliferation marker Ki67 made in the breast carcinoma during/after neoadjuvant therapy is strongly predictive of long-term disease outcome.30

Spatholobus suberectus (SS) extracts (20-80 μg/ml) were used to treat MCF7 and MDA-MB-231 cells. SS triggered apoptosis and cell cycle arrest at the G2/M phase in both cell lines after 48 hours. JC-1 staining after 50 μg/ml of SS treatment showed that mitochondrial membrane potential was lowered, indicating that apoptosis was mediated by the mitochondrial pathway. LDH-A inhibition is associated with ROS- mediated accumulation and cell death. SS could suppress LDH-A activity under normoxic and hypoxic conditions in both cancer cells in a dose- and time-dependent manner. In vivo experiments confirmed that SS significantly inhibited both cancer growth with 64.60% and 51.94% inhibition ratio on MDA-MB-231 and MCF-7 breast cancer xenografts, respectively. It was found that EGC and HIF-1α regulate LDH-A activity. EGC promotes HIF-1α degradation, which could dose-dependently inhibit tumor growth in both cancer xenografts. EGC was validated as the key compound in SS by targeting HIF-1α/LDH-A. The expression of HIF-1α, LDH-A and Ki67 were all down-regulated, while apoptosis ratio was elevated in EGC-treated tumor samples, implying that SS mediates its anti-cancer activity through HIF-1α/LDH-A inhibition and the induction of oxidative stress.16

Cervical cancer

Spatholobus Suberectus significantly inhibited the proliferation of cervical cancer cell lines in a dose-dependent and time – dependent manner. Fluorescence-activated cell soring (FACS) analysis indicated that Spatholobus Suberectus Dunn induced G1 cell cycle arrest. Spatholobus Suberectus Dunn enhanced the expression of p21waf1 and p27kip1 with cell cycle arrest. Further, Spatholobus Suberectus Dunn stimulated apoptosis via capase3 pathway. These findings suggest that SS is a candidate agent for the treatment of cervical cancer. p21waf1 and p27kip1 may play an important role in Spatholobus Suberectus Dunn-induced cell cycle arrest and cell growth inhibition.31

Uterine leiomyoma

S. suberectus inhibited leiomyomal cell proliferation significantly compared to myometrial cell proliferation. Similarly, immunohistochemical analysis showed the inhibition of transforming growth factor-beta receptor 2 in leiomyomal tissue after treatment with the fractions of the ingredient. This study by Bajracharya et al., (2009) may be helpful in developing an alternative remedy to leiomyoma with minimal side-effects compared to the current treatments.32

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