Effective ingredients, potential targets and mechanism in cancers treatment of Bushen Jiedu Sanjie recipe

Ru Jia, Xue-Qing Hu, Yan Wang, Li-Hong Zhou1,, Hua Sui, Qi Li1,, Qing Ji*

1Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. 2Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

#These authors contributed equally to this work

Introduction

According to the latest epidemiological data, cancer has been a public health problem should not be ignored [1].A large number of clinical practices and studies have shown that traditional Chinese medicine (TCM) acts as a pivotal part in cancer comprehensive therapy with its unique advantage [2-6]. Based on long-term clinical experience, Professor Li Qi, director of the oncology department, Shuguang hospital affiliated to Shanghai University of traditional Chinese medicine, established the Bushen Jiedu Sanjie Recipe (BSJDSJR), that showed great clinical effects in cancer treatment.

BSJDSJR is composed of eight herbs: Di Huang(Rehmanniae Radix Praeparata, DH) 15g, Nv Zhen Zi(Fructus Ligustri Lucidi, NZZ) 9g, Rou Cong Rong(Cistanches Herba, RCC) 9g, Ren Shen (Panax Ginseng C. A. Mey., RS) 5g, San Ci Gu (Pseudobulbus Cremastrae Seu Pleiones, SCG) 12g, Ye Pu Tao Teng(Vitis quinquangularis Rehd., YPTT) 15g, Yu Zhi Zi(Akebiae Frucyus, YZZ) 6g and Gan Cao (Licorice, GC)6g. Clinical practice indicated that BSJDSJR could effectively reduce the postoperative tumor metastasis rate of colorectal cancer, relieve the toxic and side effects of chemotherapy and improve the patients’quality of life [7]. Experiments results showed that this anti-tumor effect probably via HIPK2-P53 signaling pathway[8] and Wnt/β-catenin signaling pathway[9].Nevertheless, the mechanisms are complicated for the complicated ingredients, and further study in the specific molecular mechanism of BSJDSJR is needed.

Network Pharmacology, coined by Andrewl Hopkins[10], integrates systems biology, polypharmacology,computational biology and other multi-disciplinary technologies [11], thus forming a multi-level analytical network, which can predict possible mechanism systematically and comprehensively. The mode of“multiple targets, multiple effects, and complex diseases” is consistent with the holistic view of TCM.Moreover, it has been widespread used in modern studies of TCM.

Our research aims to analyze the active compounds,underlying drug targets and corresponding cancer therapy of BSJDSJR based on network pharmacology and bioinformatics technology. Furthermore, we would like to explore the potential molecular mechanism and effect pathways of BSJDSJR.

Materials and methods

Screening the active compounds of BSJDSJR

Based on TCMSP, TCMID, TCM-PTD, TCM Database@ Taiwan et al.. TCM database and document retrieval,the chemical components of BSJDSJR were screened.Then we derived the Oral Bioavailability (OB) and Drug-Like index (DL) of each compound in TCMSP database. OB ≥ 30% and DL ≥ 0.18 were the cutoff values to screen potential active compounds.

Oral bioavailability (F %) is the fraction of an orally administered drug that reaches systemic circulation, one of the principal pharmacokinetic properties of drugs[12]. A compound's DL is calculated to show the similarity based upon the knowledge derived from known drugs selected from Comprehensive Medicinal Chemistry (CMC) database [13]. Before target prediction, DL was used to remove unsuitable compounds and retain drug-like compounds. When DL≥0.18, it can be considered that the compound is similar to drugs in databases [14].

Constructing the active compound-target network of BSJDSJR

Potential targets of screened compounds in BSJDSJR were identified through Drugbank, TCMSP, TCMID,and other network pharmacology databases. Cytoscape 3.3 software was used to construct the active compound- target network of BSJDSJR.

Predicting cancer treatments and analyzing signaling pathways according to TCM targets

We further performed the KEGG pathway enrichment analysis of those targets using the DAVID database.Then, we also tried to find the new kinds of cancers,which can be potentially treated by BSJDSJR according to DAVID.

Results

The active compounds of BSJDSJR

Compounds of BSJDSJR were derived from TCMSP,TCMID, TCM-PTD, TCM Database @ Taiwan et al.and literature. Finally, 76 compounds in DH, 119 compounds in NZZ, 75 compounds in RCC, 190 compounds in RS, 18 compounds in SCG, 7 compounds in YPTT, 12 compounds in YZZ and 280 compounds in GC were obtained. According to OB ≥ 30% and DL ≥0.18, a total of 129 compounds were identified as the active chemical compounds of BJSDSJR, including 2 compounds in DH, 8 compounds in NZZ, 6 compounds in RCC, 18 compounds in RS, 3 compounds in SCG, 1 compound in YPTT, 4 compounds in BYZ and 87 compounds in GC (Table 1).

The active compound-target network of BSJDSJR

Drugbank database was used to collect the targets of each active compound in BSJDSJR. Cytoscape 3.3 software was used to construct the active chemical compound-target network of BSJDSJR. We have found 34 targets in DH, 195 targets in NZZ, 171 targets in RCR, 111 targets in RS, 65 targets in SCG, 1 target in YPTT, and 50 targets in BYY and 301 targets in GC(Table S1). The compound-target network includes 8 herbs, 129 compounds, 301 targets in total and has 2556 edges (Figure 1).

Cancer treatments of BSJDSJR

On the basis of the compound-target network of BSJDSJR, TCMSP database was used to screen the diseases corresponding to all targets. According to P＜0.05, the KEGG enrichment analysis results showed that BSJDSJR might treat hepatitis B/C, multiple cancers, parasitic diseases and acute or chronic myeloid leukemia et al. Top 10 cancers with the most statistical significance were bladder cancer, pancreatic cancer,non-small cell lung cancer, colorectal cancer, small cell lung cancer, endometrial cancer, prostate cancer,melanoma, glioma, renal cell cancer and thyroid cancer(Figure 2). DAVID Functional Annotation Bioinformatics Microarray Analysis Platform and KEGG pathway database were used to further explore the molecular mechanism of the active compounds of BSJDSJR in tumorigenesis and development.Cancer-related signaling pathway was found be most related to BSJDSJR, including HIF-1, TNF, PI3K-Akt,p53, ErbB, VEGF, MAPK, Jak-STAT, AMPK, NF-κB signaling pathway and so on. This is also consistent with the result that BSDSJR may treat multiple cancers.Besides, thyroid hormone signaling pathway, calcium signaling pathway, prolactin signaling pathway, and other signaling pathway were also closely related to BSJDSJR (Figure 3).

Figure 1 Active compound- target network diagram of BSJDSJR

Figure 2 Cancers related to BSJDSJR

Figure 3 Top 10 significantly enriched KEGG pathway related to BSJDSJR

Figure 4 Key targets and related signaling pathway of BSJDSJR

Signaling pathway analysis of BSJDSJR

Based on the active compound-target network of BSJDSJR constructed before, active proteins of BSJDSJR included GSK-3β, MMP-9, myc, p53, EGFR,STAT3, STAT1, Bcl2, Mcl1, Akt, Raf et al., which are key proteins in both the WNT/β-catenin signaling pathway and the STAT3 signaling pathway. Further investigation showed that various active compounds of BSJPJDR, were closely connected with COX-2/β-catenin signaling pathway, IL6 and EGF mediated STAT3 signaling pathway and MAPK/ERK signaling pathway, such as Quercetin, Formononetin,Kaempferol et al. (Figure 4).

Discussion

Network pharmacology has been widely used to explore,predict and explore the molecular mechanism of the effects of traditional Chinese medicine in cancer treatments. Several studies have analyzed and discussed the anti-tumor drug active compounds, drug targets and potential molecular mechanisms of Chun Pi (Ailanthi Cortex) [15], Bai Qu Cai (Chelidonium majus L.) [16],and Ban Zhi Lian (Scutellariae Barbatae Herba) [17]and other Chinese herbal medicines by network pharmacology method respectively. Also, there are plenty of studies analyzed the potential mechanism of TCM treatment in hepatocellular carcinoma [18], bowel cancer [19], lung cancer [20] and other cancers, which provides a basis for modern pharmacological research on the treatment of tumors by TCM.

In this study, the molecular mechanism of BSJDSJR was studied by combining network pharmacology prediction with information enrichment of bio-information database. There were 129 active compounds selected by OB and DL, and 301 targets were found through databases such as DrugBank. The active ingredient Quercetin had the most target, which is related to the regulation of multiple transcription factors [21], prostaglandin receptor [22] and coagulation factor [23]. The targets such as nuclear receptor coactivator 2 [24] and prostaglandin synthase 2(COX-2) [25] are regulated by several active compounds, of which COX-2 is the most studied, not only involved in inflammatory response [26], but also closely related to the occurrence and metastasis of tumors[27], and participates in multiple signaling pathways, such as the PKC-cMET-ERK1/2-COX-2 signaling pathway[28], COX-2/PGE2-mediated JAK2/STAT3 signaling pathway[29], COX-2-mediated EP4/PI3K/AKT/NOTCH/WNT signaling axis[30] et al.The importance of COX-2 in the development of the tumor is further suggested. The network pharmacology analysis shows that BSJDSJR has certain pharmacological effects on many diseases, which are most related to cancers, such as bladder cancer,pancreatic cancer, non-small cell lung cancer, colorectal cancer, small cell lung cancer, endometrial cancer,prostate cancer and so on, and are mostly related to cancer participated signaling pathway. After an in-depth analysis of the key signaling pathways in the development of cancer, it is found that the key active compounds of BSJDSJR, Quercetin, and Formononetin,are closely related to the Cox-2/β-catenin signaling pathway [31] and IL6/EGF- mediated STAT3 signaling pathway [32-33], and Quercetin, Kaempferol, and Formononetin were related closely with MAPK/ERK signaling pathway [34]. All the above results suggest that BSJDSJR has certain prevention and treatment effect on the progress of a tumor, but further experimental verification and clinical research evidence are needed to evaluate the effect.

Using network pharmacology and bioinformatics techniques, based on BSJDSJR, this study screened the effective active compounds and targets, constructed the drug-target network, and systematically analyzed the signaling pathway of the active compounds. At the same time, a correlation analysis was made on the cancer disease which BSJDSJR may have effects. This study provides some scientific basis for the cancer treatment of BSJDSJR.

Table 1 Compounds of BSJDSJR

MOL000006 luteolin 286.25 2.07 4 6 36.16 0.19 -0.84 0.25 0.39 15.94 MOL000098 quercetin 302.25 1.5 5 7 46.43 0.05 -0.77 0.28 0.38 14.4 MOL000358 beta-sitosterol 414.79 8.08 1 1 36.91 1.32 0.99 0.75 0.23 5.36 MOL005320 arachidonate 304.52 6.41 1 2 45.57 1.27 0.58 0.2 0.26 7.56 MOL005384 suchilactone 368.41 3.73 0 6 57.52 0.82 0.28 0.56 0.28 9.03 MOL007563 Yangambin 446.54 2.6 0 8 57.53 0.67 0.01 0.81 0.14 3.61 MOL000098 quercetin 302.25 1.5 5 7 46.43 0.05 -0.77 0.28 0.38 14.4 MOL008871 Marckine 475.69 5.3 3 5 37.05 0.86 -0.1 0.69 0.17 13.56 MOL000358 beta-sitosterol 414.79 8.08 1 1 36.91 1.32 0.99 0.75 0.23 5.36 MOL000449 Stigmasterol 412.77 7.64 1 1 43.83 1.44 1 0.76 0.22 5.57 MOL007991 2-methoxy-9,10-dihydrophenant hrene-4,5-diol 242.29 3.4 2 3 44.97 1.1 0.61 0.18 0.31 -0.81 MOL010929 glyceryl linolenate 352.57 5.15 2 4 38.14 0.32 -0.43 0.31 0.26 6.05 MOL000358 beta-sitosterol 414.79 8.08 1 1 36.91 1.32 0.99 0.75 0.23 5.36 MOL000359 sitosterol 414.79 8.08 1 1 36.91 1.32 0.87 0.75 0.22 5.37 MOL008121 2-Monoolein 356.61 6.04 2 4 34.23 0.32 -0.42 0.29 0.19 4.41 MOL002879 Diop 390.62 7.44 0 4 43.59 0.79 0.26 0.39 0.28 3.6 MOL000449 Stigmasterol 412.77 7.64 1 1 43.83 1.44 1 0.76 0.22 5.57 MOL000358 beta-sitosterol 414.79 8.08 1 1 36.91 1.32 0.99 0.75 0.23 5.36 MOL003648 Inermin 284.28 2.44 1 5 65.83 0.91 0.36 0.54 0.3 11.73 MOL000422 kaempferol 286.25 1.77 4 6 41.88 0.26 -0.55 0.24 0 14.74 MOL005308 Aposiopolamine 271.34 1.39 1 4 66.65 0.66 0.4 0.22 0.35 3.54 MOL005317 Deoxyharringtonine 515.66 3.13 1 9 39.27 0.19 -0.25 0.81 0.23 7.9 MOL005318 Dianthramine 289.26 2.05 5 7 40.45 -0.23 -0.97 0.2 0.42 5.14 MOL005320 arachidonate 304.52 6.41 1 2 45.57 1.27 0.58 0.2 0.26 7.56 MOL005321 Frutinone A 264.24 2.7 0 4 65.9 0.89 0.46 0.34 0.47 19.1 MOL005344 ginsenoside rh2 622.98 4.04 6 8 36.32 -0.51 -1.38 0.56 0.24 11.08 MOL005348 Ginsenoside-Rh4_qt 458.8 5.59 3 3 31.11 0.5 -0.18 0.78 0.25 6.97 MOL005356 Girinimbin 263.36 4.6 1 1 61.22 1.72 1.22 0.31 0.33 8.17 MOL005376 Panaxadiol 460.82 5.46 2 3 33.09 0.82 0.23 0.79 0.22 6.34 MOL005384 suchilactone 368.41 3.73 0 6 57.52 0.82 0.28 0.56 0.28 9.03 MOL005399 alexandrin_qt 414.79 8.08 1 1 36.91 1.3 0.88 0.75 0.23 5.53 MOL005401 ginsenoside Rg5_qt 442.8 6.8 2 2 39.56 0.88 0.21 0.79 0.24 5.65 MOL000787 Fumarine 353.4 2.95 0 6 59.26 0.56 -0.13 0.83 0.3 23.46 MOL001484 Inermine 284.28 2.44 1 5 75.18 0.89 0.4 0.54 0.3 11.72 MOL001792 DFV 256.27 2.57 2 4 32.76 0.51 -0.29 0.18 0.42 17.89 MOL000211 Mairin 456.78 6.52 2 3 55.38 0.73 0.22 0.78 0.26 8.87 MOL002311 Glycyrol 366.39 4.85 2 6 90.78 0.71 -0.2 0.67 0.28 9.85 MOL000239 Jaranol 314.31 2.09 2 6 50.83 0.61 -0.22 0.29 0.29 15.5

MOL002565 Medicarpin 270.3 2.66 1 4 49.22 1 0.53 0.34 0.31 8.46 MOL000354 isorhamnetin 316.28 1.76 4 7 49.6 0.31 -0.54 0.31 0.32 14.34 MOL000359 sitosterol 414.79 8.08 1 1 36.91 1.32 0.87 0.75 0.22 5.37 MOL003656 Lupiwighteone 338.38 3.92 3 5 51.64 0.68 -0.23 0.37 0.36 15.63 MOL003896 7-Methoxy-2-methyl isoflavone 266.31 3.36 0 3 42.56 1.16 0.56 0.2 0.33 16.89 MOL000392 formononetin 268.28 2.58 1 4 69.67 0.78 0.02 0.21 0 17.04 MOL000417 Calycosin 284.28 2.32 2 5 47.75 0.52 -0.43 0.24 0 17.1 MOL000422 kaempferol 286.25 1.77 4 6 41.88 0.26 -0.55 0.24 0 14.74 MOL004328 naringenin 272.27 2.3 3 5 59.29 0.28 -0.37 0.21 0.4 16.98 MOL004805(2S)-2-[4-hydroxy-3-(3-methylb ut-2-enyl)phenyl]-8,8-dimethyl-2,3-dihydropyrano[2,3-f]chrome n-4-one 390.51 5.48 1 4 31.79 1 0.25 0.72 0.35 14.82 MOL004806 euchrenone 406.56 6.35 1 4 30.29 1.09 0.39 0.57 0 15.89 MOL004808 glyasperin B 370.43 4.02 3 6 65.22 0.47 -0.09 0.44 0 16.1 MOL004810 glyasperin F 354.38 2.97 3 6 75.84 0.43 -0.15 0.54 0 15.64 MOL004811 Glyasperin C 356.45 4.73 3 5 45.56 0.71 0.07 0.4 0 3.13 MOL004814 Isotrifoliol 298.26 2.99 2 6 31.94 0.53 -0.25 0.42 0 7.91 MOL004815(E)-1-(2,4-dihydroxyphenyl)-3-(2,2-dimethylchromen-6-yl)prop-2-en-1-one 322.38 3.96 2 4 39.62 0.66 -0.12 0.35 0 16.16 MOL004820 kanzonols W 336.36 3.63 2 5 50.48 0.63 0.04 0.52 0 0.15 MOL004824(2S)-6-(2,4-dihydroxyphenyl)-2-(2-hydroxypropan-2-yl)-4-metho xy-2,3-dihydrofuro[3,2-g]chrom en-7-one 384.41 2.96 3 7 60.25 0 -0.76 0.63 0 4.31 MOL004827 Semilicoisoflavone B 352.36 2.85 3 6 48.78 0.45 -0.33 0.55 0 17.02 MOL004828 Glepidotin A 338.38 3.9 3 5 44.72 0.79 0.06 0.35 0 16.09 MOL004829 Glepidotin B 340.4 3.88 3 5 64.46 0.46 -0.09 0.34 0 15.98 MOL004833 Phaseolinisoflavan 324.4 3.95 2 4 32.01 1.01 0.46 0.45 0 2.66 MOL004835 Glypallichalcone 284.33 3.4 1 4 61.6 0.76 0.23 0.19 0 17.01 MOL004838 8-(6-hydroxy-2-benzofuranyl)-2,2-dimethyl-5-chromenol 308.35 4.2 2 4 58.44 1 0.34 0.38 0.34 8.71 MOL004841 Licochalcone B 286.3 2.88 3 5 76.76 0.47 -0.46 0.19 0 17.02 MOL004848 licochalcone G 354.43 4.35 3 5 49.25 0.64 -0.04 0.32 0.35 15.75 MOL004849 3-(2,4-dihydroxyphenyl)-8-(1,1-dimethylprop-2-enyl)-7-hydroxy-5-methoxy-coumarin 368.41 4.03 3 6 59.62 0.4 -0.23 0.43 0 0.69 MOL004855 Licoricone 382.44 4.16 2 6 63.58 0.53 -0.14 0.47 0 16.37 MOL004856 Gancaonin A 352.41 4.17 2 5 51.08 0.8 0.13 0.4 0 16.82 MOL004857 Gancaonin B 368.41 3.91 3 6 48.79 0.58 -0.1 0.45 0 16.49 MOL004863 3-(3,4-dihydroxyphenyl)-5,7-dih ydroxy-8-(3-methylbut-2-enyl)c hromone 354.38 3.65 4 6 66.37 0.52 -0.13 0.41 0 15.81 MOL004864 5,7-dihydroxy-3-(4-methoxyphe 352.41 4.17 2 5 30.49 0.9 0.21 0.41 0 14.99

nyl)-8-(3-methylbut-2-enyl)chro mone MOL004879 Glycyrin 382.44 4.67 2 6 52.61 0.59 -0.13 0.47 0 1.31 MOL004882 Licocoumarone 340.4 4.98 3 5 33.21 0.84 0.06 0.36 0 9.66 MOL004883 Licoisoflavone 354.38 3.65 4 6 41.61 0.37 -0.27 0.42 0 16.09 MOL004884 Licoisoflavone B 352.36 2.85 3 6 38.93 0.46 -0.18 0.55 0 15.73 MOL004885 licoisoflavanone 354.38 2.97 3 6 52.47 0.39 -0.22 0.54 0 15.67 MOL004891 shinpterocarpin 322.38 3.46 1 4 80.3 1.1 0.68 0.73 0.32 6.5 MOL004898(E)-3-[3,4-dihydroxy-5-(3-meth ylbut-2-enyl)phenyl]-1-(2,4-dihy droxyphenyl)prop-2-en-1-one 340.4 4.49 4 5 46.27 0.41 -0.4 0.31 0.43 15.24 MOL004903 liquiritin 418.43 0.66 5 9 65.69 -1.06 -1.93 0.74 0 17.96 MOL004904 licopyranocoumarin 384.41 3.04 3 7 80.36 0.13 -0.62 0.65 0 0.08 MOL004907 Glyzaglabrin 298.26 2.1 2 6 61.07 0.34 -0.2 0.35 0 21.2 MOL004908 Glabridin 324.4 3.95 2 4 53.25 0.97 0.36 0.47 0 0.03 MOL004910 Glabranin 324.4 4.42 2 4 52.9 0.97 0.31 0.31 0 16.24 MOL004911 Glabrene 322.38 3.77 2 4 46.27 0.99 0.04 0.44 0 3.63 MOL004912 Glabrone 336.36 3.12 2 5 52.51 0.59 -0.11 0.5 0 16.09 MOL004913 1,3-dihydroxy-9-methoxy-6-ben zofurano[3,2-c]chromenone 298.26 2.99 2 6 48.14 0.48 -0.19 0.43 0 8.87 MOL004914 1,3-dihydroxy-8,9-dimethoxy-6-benzofurano[3,2-c]chromenone 328.29 2.98 2 7 62.9 0.4 -0.34 0.53 0 9.32 MOL004915 Eurycarpin A 338.38 3.92 3 5 43.28 0.43 -0.06 0.37 0 17.1 MOL004924 (-)-Medicocarpin 432.46 0.75 4 9 40.99 -0.6 -1.34 0.95 0 13.2 MOL004935 Sigmoidin-B 356.4 3.89 4 6 34.88 0.42 -0.41 0.41 0 14.49 MOL004941 (2R)-7-hydroxy-2-(4-hydroxyph enyl)chroman-4-one 256.27 2.57 2 4 71.12 0.41 -0.25 0.18 0 18.09 MOL004945(2S)-7-hydroxy-2-(4-hydroxyph enyl)-8-(3-methylbut-2-enyl)chr oman-4-one 324.4 4.42 2 4 36.57 0.72 -0.04 0.32 0 17.95 MOL004948 Isoglycyrol 366.39 4.36 1 6 44.7 0.91 0.05 0.84 0 6.69 MOL004949 Isolicoflavonol 354.38 3.63 4 6 45.17 0.54 -0.42 0.42 0 15.55 MOL004957 HMO 268.28 2.58 1 4 38.37 0.79 0.25 0.21 0 16.56 MOL004959 1-Methoxyphaseollidin 354.43 4.25 2 5 69.98 1.01 0.48 0.64 0 9.53 MOL004961 Quercetin der. 330.31 1.82 3 7 46.45 0.39 -0.44 0.33 0 16.61 MOL004966 3'-Hydroxy-4'-O-Methylglabridi n 354.43 3.93 2 5 43.71 1 0.73 0.57 0 -0.61 MOL000497 licochalcone a 338.43 4.62 2 4 40.79 0.82 -0.21 0.29 0 16.2 MOL004974 3'-Methoxyglabridin 354.43 3.93 2 5 46.16 0.94 0.47 0.57 0 0.52 MOL004978 2-[(3R)-8,8-dimethyl-3,4-dihydr o-2H-pyrano[6,5-f]chromen-3-yl]-5-methoxyphenol 338.43 4.2 1 4 36.21 1.12 0.61 0.52 0 -0.13 MOL004980 Inflacoumarin A 322.38 4.7 2 4 39.71 0.73 -0.24 0.33 0 2.31 MOL004985 icos-5-enoic acid 310.58 7.75 1 2 30.7 1.22 1.09 0.2 0 5.28 MOL004988 Kanzonol F 420.54 5.3 1 5 32.47 1.18 0.56 0.89 0.28 9.98

Note: BSJDSJR, Bushen Jiedu Sanjie Recipe.

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