Research ArticleExperimental Studies

Traditional Chinese Medicine Xihuang Wan Inhibited Lewis Lung Carcinoma in a Syngeneic Model, Equivalent to Cytotoxic Chemotherapy, by Altering Multiple Signaling Pathways

ZHIYING ZHANG, JIANFENG WANG, HUA DUAN, DIANNA LIU, XIANGNAN ZHOU, XIMING LIN, HAOYUE PANG, MANQIANG SUN, TIAN ZHOU, ROBERT M. HOFFMAN and KAIWEN HU
In Vivo July 2021, 35 (4) 2005-2014; DOI: https://doi.org/10.21873/invivo.12469

Abstract

Background/Aim: Xihuang Wan (XHW), a traditional Chinese medicine (TCM), has been used in China for a variety of cancers including lung cancer. The present study evaluated the efficacy of XHW on a Lewis lung mouse model and explored the potential mechanism via transcriptomics. Materials and Methods: The mice were randomized into 6 groups: 1) untreated control (n=10); 2) low-dose XHW; 3) medium-dose XHW; 4) high-dose XHW; 5) cisplatin; and 6) untreated blank (n=4). Lewis lung carcinoma (LLC) cells were injected subcutaneously except for the 4 mice in the blank group. The body weight and tumor length and width were measured every 3 days. RNA-sequencing was performed on tumors in the high-dose XHW group and the control group. Results: XHW inhibited the growth of LLC in a syngeneic mouse model, without toxicity, with equivalent efficacy to cisplatin. RNA-sequencing demonstrated that many signaling pathways were involved in XHW-mediated inhibition of LLC, including tumor necrosis factor, estrogen, cyclic guanosine 3’, 5’-monophosphate-protein kinase G, apelin and the peroxisome proliferator-activated receptor signaling pathways. Conclusion: XHW inhibited LLC carcinoma through different pathways and shows clinical promise for patients who cannot tolerate platinum-based drugs.

Lung cancer, with an estimated 2.2 million new cases and 1.8 million deaths in 2020, ranks second in incidence and first in mortality among all cancer types throughout the world (1). In China, lung cancer was also the second most commonly diagnosed cancer (815,563 cases) and the leading cause of cancer death (243,153 cases) in 2020 (2). First-line treatment includes surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy (3, 4). However, lung cancer still remains recalcitrant.

In China, traditional Chinese medicine (TCM) has been used in clinical practice for thousands of years for a variety of diseases, including benign and malignant tumors (5-8). Xihuang Wan (XHW) was first recorded in the 18th-century Chinese medical book Waike Zhengzhi Quansheng Ji (Life-saving Manual of Diagnosis and Treatment of External Diseases). XHW comprises Ruxiang (Olibanum), Moyao (Myrrha), Niuhuang (Moschus), and Shexiang (Bovis Calculus). XHW has been approved by the National Medical Products Administration (NMPA) of China for the treatment of cancer (approval number Z11020073). In clinical practice, XHW has been used to treat breast (9-12), colorectal (13), liver (14, 15), cervical (16-18), and lung cancer (19-21). A systematic review and meta-analysis showed that XHW combined with chemotherapy enhanced response, prolonged overall survival, improved the quality of life of patients, and alleviated treatment-induced side effects (22).

Our laboratory has previously studied Lewis-lung carcinoma (LLC) in both nude mouse and syngeneic models (23-35). In the present study, we examined the anti-cancer efficacy of XHW in a syngeneic mouse model of LLC, and explored the potential mechanism of XHW by RNA-sequencing.

Materials and Methods

Preparation of Chinese medicine formula. Xihuang Wan (XHW) was obtained from Tongrentang (Beijing, China; Lot number: 18041283). XHW was dissolved in sodium carboxymethyl cellulose (CMC-Na) solution (5 mg/ml CMC-Na in sodium chloride for injection) at 0.493 g/ml, 0.246 g/ml, and 0.123 g/ml.

Drugs and reagents. Cisplatin was obtained from Qilu Pharmaceutical (Shandong, PR China). CMC-Na was obtained from Solarbio (Beijing, PR China). Pentobarbital sodium salt was obtained from Sigma-Aldrich (St. Louis, MO, USA). Sodium chloride for injection was obtained from Tiancheng Pharmaceutical (Hebei, PR China).

Cancer cell line. The LLC cell line LL/2 (LLC1) was purchased from KeyGEN BioTECH (Jiangsu, China). The cells were maintained in high-glucose DMEM (EallBio, Beijing, PR China) supplemented with 10% fetal bovine serum (Analysis Quiz, Beijing, PR China), penicillin (100 U/ml, EallBio) and streptomycin (100 μg/ml, EallBio) at 37°C in a CO2 incubator.

Mice. C57BL/6 mice (6-8 weeks, male) were obtained from SPF Biotechnology (Beijing, China, License No. SYXK 2019-0010). The mice were fed with an autoclaved laboratory rodent diet (SPF Biotechnology) and housed in a barrier facility in high efficacy particulate air (HEPA)-filtered racks under standard conditions of 12-h light/dark cycles. The mice were anesthetized by peritoneal injection of pentobarbital sodium at a dose of 50 mg/kg. The response of the mice was monitored to ensure adequate depth of anesthesia. The animals were observed daily and sacrificed by CO2 inhalation if the following humane end point criteria were met: severe tumor burden (over 20 mm in diameter), significant body weight loss, body temperature drop, difficulty in breathing, prostration and rotational motion. The present study was conducted in accordance with the Guidelines of Welfare and Ethics of Laboratory Animals (IACUC Issue No. AW2020111001) by SPF Biotechnology (36).

Experimental design. Fifty-four mice were randomized into 6 groups: 1) untreated control (n=10); 2) low-dose XHW [0.617 g/kg, oral gavage (p.o.), n=10]; 3) medium-dose XHW (1.233 g/kg, p.o., n=10); 4) high-dose XHW (2.466 g/kg, p.o., n=10); and 5) cisplatin [3 mg/kg, intraperitoneal injection (i.p.), n=10]; and 6) the blank group (n=4). LLC cells (1×106/200 μl) were injected subcutaneously into the right flank of the mice, except for the 4 mice in the blank group (37, 38). Treatment was started the next day. Details of the treatment protocol are presented in Table I. The condition of the mice was monitored every day. The body weight and the tumor length and width were measured every 3 days. When the diameter of the tumor reached 20 mm, drug administration was stopped, and the mice were sacrificed. The tumor, spleen, liver, lung and thymus were removed and weighed. The tumor volume was calculated with the following formula: 0.5*Length*Width2 (39). The ratios of organ weight to body weight (spleen, liver, lung, and thymus) were calculated to determine whether there was treatment-associated toxicity.

View this table:
Table I.

Treatment protocol.

Histological examination and Ki-67 immunohistochemical staining. Freshly-harvested tumors and the livers were fixed in 10% formalin and embedded in paraffin for further histology analysis. Hematoxylin and eosin (H&E) staining and immunochemical staining were performed according to standard protocols (40, 41). Ki-67 staining was performed with a primary anti-Ki-67 antibody (1:200; Abcam, Cambridge, UK). The Ki-67 index was calculated as the percentage of positively stained cancer cells among all cancer cells. The images were obtained with a Leica Microsystems DM3000 (Leica Camera AG, Wetzlar, Germany) with CIM-2 software without post-acquisition processing.

RNA-sequencing analysis. The freshly removed tumors in the control group and high-dose XHW group were frozen in liquid nitrogen and then sent to the Beijing Genomics Institute (BGI, Shenzhen, PR China) for RNA-sequencing. Three parallel replicates of each sample were analyzed. RNA-sequencing was performed using the DNBSEQ platform (BGI). The data were analyzed on the Dr. Tom II network platform of the BGI (https://biosys.bgi.com/). The sequencing data were filtered with SOAPnuke (v1.5.2) (42) to remove reads containing sequencing adapter, reads with a low-quality base ratio (base quality less than or equal to 5) of more than 20%, and reads whose unknown base (‘N’ base) ratio was more than 5%. The clean reads were obtained and stored in FASTQ format. The clean reads were mapped to the reference genome using HISAT2 (v2.0.4) (43). Bowtie2 (v2.2.5) (44) was applied to align the clean reads to the reference coding gene set, then the expression levels of the genes were calculated by RSEM (v1.2.12) (45). Essentially, differential expression analysis was performed using the DEGseq (v1.44.0) (46) with a Q value ≤0.001. KEGG (https://www.kegg.jp/) enrichment analysis of annotated differentially expressed genes was performed by Phyper (https://en.wikipedia.org/wiki/Hypergeometric_distribution) based on the Hypergeometric test. The significant levels of terms and pathways were corrected by Q value with a rigorous threshold (Q value ≤0.05) determined by the Bonferroni analysis (47).

Statistical analysis. All statistical analyses were performed by SPSS Statistics 26 (IBM, New York City, NY, USA). The Shapiro-Wilk test was used to assess the normal distribution. The Bartlett’s test was used to verify the homogeneity of variances among groups. One-way ANOVA with LSD for post hoc analysis was used for the parametric test. The Kruskal-Wallis one-way ANOVA with Steel-Dwass for post hoc analysis was used for the non-parametric comparison. The experimental data are expressed as the mean±standard deviation (SD). A p-value of 0.05 or less was considered statistically significant.

Results

Efficacy of treatment on the LLC tumor. XHW inhibited LLC tumor growth to a similar extent as cisplatin in the syngeneic model. Tumor volume in the cisplatin and the high-dose XHW groups were significantly smaller that in the control group (p<0.01 and p<0.05 respectively). Tumor weights in the cisplatin and high-dose XHW groups were also significantly smaller than that in the control group (p<0.01 and p<0.05 respectively) (Figure 1A and B).

Figure 1.
Figure 1.

Efficacy of treatment on the Lewis lung carcinoma (LLC). A: Growth curve of tumor volume. B: Efficacy of treatment on the LLC tumor weight. *p<0.05; **p<0.01.

Effect of treatment on body and organ weight. There was no significant change of body weight in any group during the 15-day drug administration period. The mice treated with high-dose XHW had the largest livers among the tumor-bearing mice (p<0.001). There was no statistically significant difference in the size of the spleen, lung, and thymus among the different groups (Figure 2A and B).

Figure 2.
Figure 2.

Effect of treatment on body weight and organ weight ratio. A: Body weight. B: Organ ratio (spleen, liver, lung and thymus). *p<0.05 vs. control; ##p<0.01 vs. blank; ###p<0.001 vs. blank.

Effect of treatment on histology. Under light microscopy, LLC cells in the untreated control group were densely arranged with obvious anaplastic characteristics: various cell sizes and diverse morphologies; variable cell nuclei sizes and increased nucleus to cytoplasm ratio; granular chromatin and uneven distribution. Pathological mitoses such as multipolar and asymmetric nuclear divisions were observed. In the cisplatin group, more cells showed morphological changes associated with apoptosis including chromatin aggregation, nuclear consolidation, nuclear fragmentation and lysis. In the high-dose XHW and cisplatin group, necrotic areas were observed (Figure 3).

Figure 3.
Figure 3.

Effect of treatment on tumor histology. Hematoxylin and eosin staining was performed according to standard protocols. Under light microscopy, LLC cells in the untreated control group were densely arranged with obvious anaplastic characteristics: various cell sizes and diverse morphologies; variable cell nuclei sizes and increased nucleus to cytoplasm ratio; granular chromatin and uneven distribution. Pathological mitoses such as multipolar and asymmetric nuclear divisions were observed. In the cisplatin group, more cells showed morphological changes associated with apoptosis including chromatin aggregation, nuclear consolidation, nuclear fragmentation and lysis. In the high-dose XHW and cisplatin group, necrotic areas were observed. Scale bar: 50 μm.

Although the liver index was larger in each group compared to that in the blank group, there was no significant difference in liver histology among all groups. All groups had normal liver parenchyma with unremarkable hepatocytes having vacuolated cytoplasm, bland nuclei, and punctate nucleoli (Figure 4).

Figure 4.
Figure 4.

Effect of treatment on liver histology. Freshly-harvested livers were fixed in 10% formalin and embedded in paraffin and stained with hematoxylin and eosin. All groups had normal liver parenchyma with unremarkable hepatocytes having vacuolated cytoplasm, bland nuclei, and punctate nucleoli. There was no significant difference in liver histology among all groups. Scale bar: 50 μm.

Effect of treatment on Ki-67 index. The Ki-67 index in the control group was 7.35%±0.90%, which was significantly greater than that in the cisplatin group (1.31%±1.04%, p<0.001), the low-dose XHW group (1.94%±0.25%, p<0.001), the medium-dose XHW group (1.50%±0.33%, p<0.001), and the high-dose XHW group (1.87%±0.43%, p<0.001) (Figure 5).

Figure 5.
Figure 5.

Effect of treatment on the Ki-67 index. Ki-67 staining was performed with a primary anti-Ki-67 antibody. The Ki-67 index was calculated as the percentage of positively stained cancer cells among all cancer cells. The Ki-67 index in the control group was significantly greater than that in the cisplatin, the low-dose XHW, the medium-dose XHW, and the high-dose XHW group.

RNA-sequencing analysis. An average of 23.12 Mb clean reads, with an average genome mapping rate of 96.41%, was obtained. There were 406 differentially expressed genes between the control group and high-dose XHW group (|log2FC| ≥1, Q value ≤0.001), 130 genes were up-regulated, 276 genes were down-regulated (Figure 6A). The KEGG pathway cluster analysis showed that the 406 genes were closely associated with multiple signaling pathways, including tumor necrosis factor (TNF), estrogen, cyclic guanosine 3’, 5’-monophosphate-protein kinase G (cGMP-PKG), apelin and the peroxisome proliferator-activated receptor (PPAR) signaling pathways (Figure 6B).

Figure 6.
Figure 6.

Effect of high-dose XHW on gene expression. A) Volcano map of differentially expressed genes between the control group and the high-dose XHW group. There were 406 differentially expressed genes (|log2FC|≥1, Q value ≤0.01), 130 genes were up-regulated, 276 genes were down-regulated. B) KEGG pathway cluster analysis based on the 406 genes was significantly changed as described in A.

Discussion

The present study showed that XHW inhibited the growth of LLC in a syngeneic mouse model, and reduced the Ki-67 index, indicating that XHW alone could inhibit lung cancer. XHW alone was at least as effective as the first-line cytotoxic drug cisplatin both on tumor growth inhibition and decrease in the Ki-67 index. No toxicity was observed in histology among all groups. Thus, XHW is a candidate to replace cisplatin in lung cancer treatment. This may become very important clinically since many patients cannot tolerate platinum-based drugs.

A previous study on XHW treatment of LLC cells indicated that 11 metabolites were differentially expressed compared to the untreated control, including L-phenylalanine, L-tryptophan, farnesylcysteine, LysoPC(18:1(9Z)/0:0, L-adrenaline, 4-maleylacetoacetate, guanosine, aminoimidazole ribotide, corticosterone, sphingosine-1-phosphate and D-urobilinogen (48), suggesting that XHW plays a major role in altering aromatic amino-acid metabolism in the LLC mouse model.

Previous studies showed that XHW induced apoptosis of human glioblastoma U-87 MG cells via targeting the ROS-activated Akt/mTOR/FOXO1 pathway (49), and potentiated the efficacy of temozolomide on a glioblastoma xenograft through the Akt/mTOR pathway (50). XHW has also been shown to promote apoptosis of Treg cells in the tumor microenvironment in a 4T1 breast-cancer mouse model by upregulating the MEKK1/SEK1/JNK1/AP-1 pathway (51). A systems pharmacology and proteomics study of XHW on triple-negative breast cancer (TNBC) showed that XHW may be effective on non-small cell lung cancer and small cell lung cancer, as demonstrated by the KEGG signaling pathway enrichment analysis (52).

In the present study, to further explore the mechanism of XHW inhibition of LLC in a syngeneic mouse model, RNA-sequencing (RNA-seq) was performed. RNA-seq demonstrated that many signaling pathways were involved, including TNF, estrogen, cGMP-PKG, apelin and PPAR signaling pathways. A previous transcriptomics and chemical informatics study showed that the TNF and estrogen signaling pathways were also involved in XHW-mediated inhibition of TNBC (53). Estrogen and the estrogen receptor have the potential to become prognosticators and therapeutic targets in lung cancer (54). Another previous study examining the effect of XHW on multiple cancers by network pharmacology showed that one of the key targets of XHW is estrogen receptor 1 (ESR1) (55). The TNF signaling pathway is involved in many physiological and pathological processes, including cell proliferation, apoptosis, regulation of immune responses and inflammation (56), closely related to cancer, including lung cancer (57). Apelin, a transmembrane G protein-coupled receptor, is an endogenous ligand of the apelin receptor, and is upregulated in multiple cancer types including lung cancer, colon cancer, gastroesophageal cancer, hepatocellular carcinoma and brain cancer (58). Down-regulation of apelin has been shown to inhibit mammary and lung cancer growth as well as lung metastasis (59). PPARs are nuclear hormone receptors activated by fatty acids and their derivatives, PPARγ is expressed in various cancer types including lung cancer. Reduced PPARγ and elevated cyclooxygenase-2 (COX-2) expression are associated with poor prognosis in lung cancer patients. PPARγ is considered to be a therapeutic target for lung cancer (60-62). Cyclic GMP (cGMP) is an intracellular second messenger, mediating the action of nitric oxide (NO) and natriuretic peptides (NPs). cGMP has been shown to exert its physiological action through cGMP-dependent protein kinase (PKG), cGMP-regulated phosphodiesterases (PDE2, PDE3) and cGMP-gated cation channels. The cGMP-PKG pathway has been found to be closely related to lung cancer (63, 64).

The RNA-seq results and KEGG pathway enrichment analysis of the present study showed that many signaling pathways were altered following treatment of the syngeneic LLC mouse model with XHW, indicating that XHW inhibited the LLC carcinoma through many different pathways. These pathways need to be further studied, including their interaction, to develop an improved therapy for lung cancer.

Acknowledgements

This study was supported by Horizontal Scientific Research Project of Dongfang Hospital, Beijing University of Chinese Medicine (No. 040101003063).

Footnotes

  • This article is freely accessible online.

  • Authors’ Contributions

    ZZ and ZT designed the study. ZZ, WJ, DH, LD, ZX, PH and SM performed the experiments. ZZ and LX analyzed the data. ZZ and ZX drafted the article. RMH revised the article and rewrote the Discussion. HK administrated and supervised the study.

  • Conflicts of Interest

    All the Authors declare no conflicts of interest in relation to this study.

  • Received May 16, 2021.
  • Revision received May 27, 2021.
  • Accepted May 31, 2021.

References

  1. ↵
    1. Sung H,
    2. Ferlay J,
    3. Siegel RL,
    4. Laversanne M,
    5. Soerjomataram I,
    6. Jemal A and
    7. Bray F
    : Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3): 209-249, 2021. PMID: 33538338. DOI: 10.3322/caac.21660
    OpenUrlCrossRefPubMed
  2. ↵
    1. Ferlay J,
    2. Ervik M,
    3. Lam F,
    4. Colombet M,
    5. Mery L,
    6. Piñeros M,
    7. Znaor A,
    8. Soerjomataram I and
    9. Bray F
    : Global Cancer Observatory: Cancer Today. Available at: http://gco.iarc.fr/today [Last accessed on February 19, 2021]
  3. ↵
    1. National Comprehensive Cancer Network
    : Non-small cell lung cancer (Version 3.2021). Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf [Last accessed on February 23, 2021]
  4. ↵
    1. National Comprehensive Cancer Network
    : Small cell lung cancer (Version 2.2021). Available at: https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf [Last accessed on February 23, 2021]
  5. ↵
    1. He J,
    2. Yin P and
    3. Xu K
    : Effect and molecular mechanisms of traditional Chinese medicine on tumor targeting tumor-associated macrophages. Drug Des Devel Ther 14: 907-919, 2020. PMID: 32184560. DOI: 10.2147/DDDT.S223646
    OpenUrlCrossRefPubMed
    1. Xiang Y,
    2. Guo Z,
    3. Zhu P,
    4. Chen J and
    5. Huang Y
    : Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science. Cancer Med 8(5): 1958-1975, 2019. PMID: 30945475. DOI: 10.1002/cam4.2108
    OpenUrlCrossRefPubMed
    1. Luo H,
    2. Vong CT,
    3. Chen H,
    4. Gao Y,
    5. Lyu P,
    6. Qiu L,
    7. Zhao M,
    8. Liu Q,
    9. Cheng Z,
    10. Zou J,
    11. Yao P,
    12. Gao C,
    13. Wei J,
    14. Ung COL,
    15. Wang S,
    16. Zhong Z and
    17. Wang Y
    : Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine. Chin Med 14: 48, 2019. PMID: 31719837. DOI: 10.1186/s13020-019-0270-9
    OpenUrlCrossRefPubMed
  8. ↵
    1. Ling CQ,
    2. Yue XQ and
    3. Ling C
    : Three advantages of using traditional Chinese medicine to prevent and treat tumor. J Integr Med 12(4): 331-335, 2014. PMID: 25074882. DOI: 10.1016/S2095-4964(14)60038-8
    OpenUrlCrossRefPubMed
  9. ↵
    1. Xu W,
    2. Ding S,
    3. Xu ningning,
    4. Shi L and
    5. Qi B
    : Therapeutic effects of Xihuang Pills combined with GP chemotherapy on advanced breast cancer. Hebei Med J 42: 1358-1361, 2020 (in Chinese). Available at: https://chn.oversea.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2020&filename=HBYZ202009018&v=2JUXz59LHYVOrG0SqVe%25mmd2BQq%25mmd2BkeCleRUf95lPhusEzMOmrPTo5perCDUhGm%25mmd2F%25mmd2FRtxM4 [Last accessed on May 31, 2021]
    OpenUrl
    1. Wu J and
    2. Wang D
    : Clinical study on xihuang capsules combined with TEC chemotherapy scheme for breast cancer of stage Ⅲ and its effect on immune function. J N Chin Med 52: 117-119, 2020. DOI: 10.13457/j.cnki.jncm.2020.12.035
    OpenUrlCrossRef
    1. Qian W,
    2. Li Z,
    3. Li R,
    4. Zhao Y,
    5. Xiao H,
    6. Si H,
    7. Chen X,
    8. Fang Y and
    9. Wu Z
    : Effect of xihuang pill combined with TP regimen in treatment of advanced breast cancer. Liaoning J Traditional Chin Med 47: 115-117, 2020 (in Chinese). Available at: https://chn.oversea.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2020&filename=LNZY202006038&v=VIkb2pgOmHDvOn6LToVyb8wR8JmTdopTf5wPsNJKn9%25mmd2Bv9%25mmd2F7eeJgt1M%25mmd2BBZhP8e%25mmd2Bvp [Last accessed on May 31, 2021]
    OpenUrl
  12. ↵
    1. Jin J and
    2. Li Z
    : Integrated Xihuang Pills and chemotherapy in treating 30 patients with breast cancer. Chin J Traditional Chin Med Pharm 25: 715-716, 2010 (in Chinese). Available at: https://chn.oversea.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2010&filename=BXYY201005027&v=CvOM3FgCJkQBycg4%25mmd2BfC0CAaUNi2APi1G0oFuMOQ7pEr7r37cLhcblgVC6ycAURlM [Last accessed on May 31, 2021]
    OpenUrl
  13. ↵
    1. Yu D and
    2. An GY
    : Clinical effects of Xihuang pill combined with chemotherapy in patients with advanced colorectal cancer. Evid Based Complement Alternat Med 2017: 5936086, 2017. PMID: 28458715. DOI: 10.1155/2017/5936086
    OpenUrlCrossRefPubMed
  14. ↵
    1. Zhou Y
    : Effect of xihuang pills in adjuvant treatment of advanced primary liver cancer. Chin J Clin Ration Drug Use 13: 73-75, 2020 (in Chinese). Available at: https://chn.oversea.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2020&filename=PLHY202004041&v=jhCilz52XxzJ8D8IJM63eS%25mmd2B9tMunWHppZosGFrrnCS%25mmd2BnAsh4Bkqt94qLk1hkSO1f [Last accessed on May 31, 2021]
    OpenUrl
  15. ↵
    1. Liu B,
    2. Yu S,
    3. Xing L,
    4. Zhao X,
    5. Lv Y and
    6. Gao Q
    : Analysis of therapeutical effects of Xihuang Pills with intraarterial intervention chemotherapy on 80 cases of advanced primary hepatic carcinoma. China J Traditional Chin Med Pharm 25: 947-948, 2010 (in Chinese). Available at: https://chn.oversea.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2010&filename=BXYY201006050&v=CvOM3FgCJkRcWaomMUz6GDZ7riVXwU6bcrgodk7DcyjkUBxYsNXeLQhTKWcR4jMB [Last accessed on May 31, 2021]
    OpenUrl
  16. ↵
    1. Zhang G
    : Analysis of the effect of xihuangwan combined with TP chemotherapy on advanced cervical cancer. China Foreign Med Treat 39: 11-14, 2020 (in Chinese). Available at: https://chn.oversea.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFD&dbname=CJFDAUTO&filename=HZZZ202019004&v=wQoMT%25mmd2BEVQT%25mmd2FOnHhWycRwx4UBgK81AdQIlWTikRTzizGNqYbwt5%25mmd2FPxkaIjgSxcLBW [Last accessed on May 31, 2021]
    OpenUrl
    1. Shao X
    : Effects of Xihuang Pill combined with neoadjuvant chemotherapy on the prognosis and Th1/Th2 cytokines in patients with advanced cervical cancer. Chin J Ration Drug Use 17: 92-96, 2020 (in Chinese). Available at: (https://chn.oversea.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2020&filename=ZYYS202006022&v=d7lumuE8ajmOqxuiesLm%25mmd2BkAPfjgjJmE2j%25mmd2BRwj9KN0bQrZGGes%25mmd2FlZTShL0eM2xvHL [Last accessed on May 31, 2021]
    OpenUrl
  18. ↵
    1. Li L and
    2. Ke X
    : Effect of Xihuang Capsule combined with radiotherapy on 45 cases of cervical cancer. Acta Chin Med Pharmacol 37: 78-79, 2009 (in Chinese). Available at: https://chn.oversea.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2009&filename=ZYXB200904035&v=W%25mmd2BUQAkAI%25mmd2Fvl%25mmd2BOwGLZCsizGLJq114RW%25mmd2FNI6wtCLn7xiihP%25mmd2FSkogCh5bVS87bflquA [Last accessed on May 31, 2021]
    OpenUrl
  19. ↵
    1. He S,
    2. Gao Y,
    3. Jin X,
    4. Wang Y,
    5. Zhang F and
    6. Liu B
    : Effect of vinorelbine+cisplatin chemotherapy combined with Xihuang Pills in the treatment of lung squamous cell carcinoma. Clin J Med Officers 48: 305-306, 2020 (in Chinese). Available at: (https://chn.oversea.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2020&filename=JYGZ202003022&v=sSmQnTLRqPYyS9rSwJK2MFaXtGy5YfOC50CgA5FFYCgN5EU6uJSOLZW9224%25mmd2BJqsV [Last accessed on May 31, 2021]
    OpenUrl
    1. Chen Y
    : Efficacy and safety of Xihuang Capsule combined with chemotherapy in the treatment of advanced lung adenocarcinoma. Med Diet Health 18: 12-13, 2020 (in Chinese). Available at: https://chn.oversea.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2020&filename=YXSL202011008&v=K2j%25mmd2BVjy9XFnGA1VpHW41mniwxxrnx5ShQ%25mmd2FqFUy9U6FhflPsa6409UExLjVenQsEl [Last accessed on May 31, 2021]
    OpenUrl
  21. ↵
    1. Cen H
    : Clinical trial of Xihuang pill combined with irinotecan and cisplatin chemotherapy in the treatment of limited stage small cell lung cancer. Chin J Clin Pharmacol 33: 1307-1310, 2017 (in Chinese). Available at: https://chn.oversea.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2017&filename=GLYZ201714006&v=PovXhSV%25mmd2B2SK4wFw54rxsd9nDL0sZjpO77KYdYCkRzw92wNnIoOgG17JuLz5utNRA [Last accessed on May 31, 2021]
    OpenUrl
  22. ↵
    1. Guo Q,
    2. Xu X,
    3. He S,
    4. Yuan Y,
    5. Chen S and
    6. Hua B
    : Xi huang pills enhance the tumor treatment efficacy when combined with chemotherapy: A meta-analysis and systematic review. J Cancer Res Ther 14(Suppl): S1012-S1018, 2018. PMID: 30539838. DOI: 10.4103/0973-1482.192795
    OpenUrlCrossRefPubMed
  23. ↵
    1. Yang M,
    2. Jiang P and
    3. Hoffman RM
    : Whole-body subcellular multicolor imaging of tumor-host interaction and drug response in real time. Cancer Res 67(11): 5195-5200, 2007. PMID: 17545599. DOI: 10.1158/0008-5472.CAN-06-4590
    OpenUrlAbstract/FREE Full Text
    1. Zhang Y,
    2. Zhang N,
    3. Zhao M and
    4. Hoffman RM
    : Comparison of the selective targeting efficacy of Salmonella typhimurium A1-R and VNP20009 on the Lewis lung carcinoma in nude mice. Oncotarget 6(16): 14625-14631, 2015. PMID: 25714030. DOI: 10.18632/oncotarget.3342
    OpenUrlCrossRefPubMed
    1. Yoshioka T,
    2. Wada T,
    3. Uchida N,
    4. Maki H,
    5. Yoshida H,
    6. Ide N,
    7. Kasai H,
    8. Hojo K,
    9. Shono K,
    10. Maekawa R,
    11. Yagi S,
    12. Hoffman RM and
    13. Sugita K
    : Anticancer efficacy in vivo and in vitro, synergy with 5-fluorouracil, and safety of recombinant methioninase. Cancer Res 58(12): 2583-2587, 1998. PMID: 9635582.
    OpenUrlAbstract/FREE Full Text
    1. Yang M,
    2. Baranov E,
    3. Li XM,
    4. Wang JW,
    5. Jiang P,
    6. Li L,
    7. Moossa AR,
    8. Penman S and
    9. Hoffman RM
    : Whole-body and intravital optical imaging of angiogenesis in orthotopically implanted tumors. Proc Natl Acad Sci USA 98(5): 2616-2621, 2001. PMID: 11226288. DOI: 10.1073/pnas.051626698
    OpenUrlAbstract/FREE Full Text
    1. Liu F,
    2. Zhang L,
    3. Hoffman RM and
    4. Zhao M
    : Vessel destruction by tumor-targeting Salmonella typhimurium A1-R is enhanced by high tumor vascularity. Cell Cycle 9(22): 4518-4524, 2010. PMID: 21135579. DOI: 10.4161/cc.9.22.13744
    OpenUrlCrossRefPubMed
    1. Zhao M,
    2. Suetsugu A,
    3. Ma H,
    4. Zhang L,
    5. Liu F,
    6. Zhang Y,
    7. Tran B and
    8. Hoffman RM
    : Efficacy against lung metastasis with a tumor-targeting mutant of Salmonella typhimurium in immunocompetent mice. Cell Cycle 11(1): 187-193, 2012. PMID: 22186786. DOI: 10.4161/cc.11.1.18667
    OpenUrlCrossRefPubMed
    1. Uchugonova A,
    2. Zhao M,
    3. Zhang Y,
    4. Weinigel M,
    5. König K and
    6. Hoffman RM
    : Cancer-cell killing by engineered Salmonella imaged by multiphoton tomography in live mice. Anticancer Res 32(10): 4331-4337, 2012. PMID: 23060555.
    OpenUrlAbstract/FREE Full Text
    1. Li L,
    2. Wang M,
    3. Yu G,
    4. Chen P,
    5. Li H,
    6. Wei D,
    7. Zhu J,
    8. Xie L,
    9. Jia H,
    10. Shi J,
    11. Li C,
    12. Yao W,
    13. Wang Y,
    14. Gao Q,
    15. Jeong LS,
    16. Lee HW,
    17. Yu J,
    18. Hu F,
    19. Mei J,
    20. Wang P,
    21. Chu Y,
    22. Qi H,
    23. Yang M,
    24. Dong Z,
    25. Sun Y,
    26. Hoffman RM and
    27. Jia L
    : Overactivated neddylation pathway as a therapeutic target in lung cancer. J Natl Cancer Inst 106(6): dju083, 2014. PMID: 24853380. DOI: 10.1093/jnci/dju083
    OpenUrlCrossRefPubMed
    1. Yang M,
    2. Baranov E,
    3. Wang JW,
    4. Jiang P,
    5. Wang X,
    6. Sun FX,
    7. Bouvet M,
    8. Moossa AR,
    9. Penman S and
    10. Hoffman RM
    : Direct external imaging of nascent cancer, tumor progression, angiogenesis, and metastasis on internal organs in the fluorescent orthotopic model. Proc Natl Acad Sci USA 99(6): 3824-3829, 2002. PMID: 11891294. DOI: 10.1073/pnas.052029099
    OpenUrlAbstract/FREE Full Text
    1. Zhou L,
    2. Jiang Y,
    3. Liu X,
    4. Li L,
    5. Yang X,
    6. Dong C,
    7. Liu X,
    8. Lin Y,
    9. Li Y,
    10. Yu J,
    11. He R,
    12. Huang S,
    13. Liu G,
    14. Zhang Y,
    15. Jeong LS,
    16. Hoffman RM and
    17. Jia L
    : Promotion of tumor-associated macrophages infiltration by elevated neddylation pathway via NF-κB-CCL2 signaling in lung cancer. Oncogene 38(29): 5792-5804, 2019. PMID: 31243299. DOI: 10.1038/s41388-019-0840-4
    OpenUrlCrossRefPubMed
    1. Pilch J,
    2. Brown DM,
    3. Komatsu M,
    4. Järvinen TA,
    5. Yang M,
    6. Peters D,
    7. Hoffman RM and
    8. Ruoslahti E
    : Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds. Proc Natl Acad Sci USA 103(8): 2800-2804, 2006. PMID: 16476999. DOI: 10.1073/pnas.0511219103
    OpenUrlAbstract/FREE Full Text
    1. Momiyama M,
    2. Suetsugu A,
    3. Kimura H,
    4. Kishimoto H,
    5. Aki R,
    6. Yamada A,
    7. Sakurada H,
    8. Chishima T,
    9. Bouvet M,
    10. Endo I and
    11. Hoffman RM
    : Imaging the efficacy of UVC irradiation on superficial brain tumors and metastasis in live mice at the subcellular level. J Cell Biochem 114(2): 428-434, 2013. PMID: 22961687. DOI: 10.1002/jcb.24381
    OpenUrlCrossRefPubMed
  35. ↵
    1. Jiang Y,
    2. Liang Y,
    3. Li L,
    4. Zhou L,
    5. Cheng W,
    6. Yang X,
    7. Yang X,
    8. Qi H,
    9. Yu J,
    10. Jeong LS,
    11. Hoffman RM,
    12. Zheng P and
    13. Jia L
    : Targeting neddylation inhibits intravascular survival and extravasation of cancer cells to prevent lung-cancer metastasis. Cell Biol Toxicol 35(3): 233-245, 2019. PMID: 31140025. DOI: 10.1007/s10565-019-09472-w
    OpenUrlCrossRefPubMed
  36. ↵
    1. MacArthur Clark JA and
    2. Sun D
    : Guidelines for the ethical review of laboratory animal welfare People’s Republic of China National Standard GB/T 35892-2018 [Issued 6 February 2018 Effective from 1 September 2018]. Animal Model Exp Med 3(1): 103-113, 2020. PMID: 32318667. DOI: 10.1002/ame2.12111
    OpenUrlCrossRefPubMed
  37. ↵
    1. Huang J,
    2. Huang X,
    3. Chen Z,
    4. Zheng Q and
    5. Sun R
    : Dose conversion among different animals and healthy volunteers in pharmacological study. Chin J Clin Pharmacol Therap 1069-1072, 2004. Available at: https://chn.oversea.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFD&dbname=CJFD2004&filename=YLZL200409025&v=8JbFNEeC3Akj5OoHiiwbr2siTNZH0gVXTEk5G6m38RILVKXJwOEsewcn5WleKw02 [Last accessed on May 31, 2021]
  38. ↵
    1. van Moorsel CJ,
    2. Pinedo HM,
    3. Veerman G,
    4. Vermorken JB,
    5. Postmus PE and
    6. Peters GJ
    : Scheduling of gemcitabine and cisplatin in Lewis lung tumour bearing mice. Eur J Cancer 35(5): 808-814, 1999. PMID: 10505043. DOI: 10.1016/s0959-8049(99)00004-0
    OpenUrlCrossRefPubMed
  39. ↵
    1. Zhang Z,
    2. Hu K,
    3. Kiyuna T,
    4. Miyake K,
    5. Kawaguchi K,
    6. Igarashi K,
    7. Nelson SD,
    8. Li Y,
    9. Singh SR and
    10. Hoffman RM
    : A patient-derived orthotopic xenograft (PDOX) nude-mouse model precisely identifies effective and ineffective therapies for recurrent leiomyosarcoma. Pharmacol Res 142: 169-175, 2019. PMID: 30807865. DOI: 10.1016/j.phrs.2019.02.021
    OpenUrlCrossRefPubMed
  40. ↵
    1. Cardiff RD,
    2. Miller CH and
    3. Munn RJ
    : Manual hematoxylin and eosin staining of mouse tissue sections. Cold Spring Harb Protoc 2014(6): 655-658, 2014. PMID: 24890205. DOI: 10.1101/pdb.prot073411ID:28849123. DOI: 10.3892/mmr.2017.7290
    OpenUrlCrossRefPubMed
  41. ↵
    1. Kim SW,
    2. Roh J and
    3. Park CS
    : Immunohistochemistry for pathologists: Protocols, pitfalls, and tips. J Pathol Transl Med 50(6): 411-418, 2016. PMID: 27809448. DOI: 10.4132/jptm.2016.08.08
    OpenUrlCrossRefPubMed
  42. ↵
    1. Li R,
    2. Li Y,
    3. Kristiansen K and
    4. Wang J
    : SOAP: short oligonucleotide alignment program. Bioinformatics 24(5): 713-714, 2008. PMID: 18227114. DOI: 10.1093/bioinformatics/btn025
    OpenUrlCrossRefPubMed
  43. ↵
    1. Kim D,
    2. Langmead B and
    3. Salzberg SL
    : HISAT: a fast spliced aligner with low memory requirements. Nat Methods 12(4): 357-360, 2015. PMID: 25751142. DOI: 10.1038/nmeth.3317
    OpenUrlCrossRefPubMed
  44. ↵
    1. Langmead B and
    2. Salzberg SL
    : Fast gapped-read alignment with Bowtie 2. Nat Methods 9(4): 357-359, 2012. PMID: 22388286. DOI: 10.1038/nmeth.1923
    OpenUrlCrossRefPubMed
  45. ↵
    1. Li B and
    2. Dewey CN
    : RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12: 323, 2011. PMID: 21816040. DOI: 10.1186/1471-2105-12-323
    OpenUrlCrossRefPubMed
  46. ↵
    1. Wang L,
    2. Feng Z,
    3. Wang X,
    4. Wang X and
    5. Zhang X
    : DEGseq: an R package for identifying differentially expressed genes from RNA-seq data. Bioinformatics 26(1): 136-138, 2010. PMID: 19855105. DOI: 10.1093/bioinformatics/btp612
    OpenUrlCrossRefPubMed
  47. ↵
    1. N Salkind
    1. Abdi H
    : The Bonferonni and Šidák corrections for multiple comparisons. In: Encyclopedia of measurement and statistics. N Salkind (eds.). Thousand Oaks, CA, USA, Sage, 2007.
  48. ↵
    1. Li C,
    2. Chen W,
    3. Zhang M,
    4. Zhang C,
    5. Cao B,
    6. Dong B,
    7. Qi S,
    8. Zhang Y,
    9. Fei X,
    10. Li X,
    11. Li R,
    12. Wang J and
    13. Li G
    : Modulatory effects of Xihuang Pill on lung cancer treatment by an integrative approach. Biomed Pharmacother 130: 110533, 2020. PMID: 32739739. DOI: 10.1016/j.biopha.2020.110533
    OpenUrlCrossRefPubMed
  49. ↵
    1. Shao M,
    2. He Z,
    3. Yin Z,
    4. Ma P,
    5. Xiao Q,
    6. Song Y,
    7. Huang Z,
    8. Ma Y,
    9. Qiu Y,
    10. Zhao A,
    11. Zhou T and
    12. Wang Q
    : Xihuang pill induces apoptosis of human glioblastoma U-87 MG cells via targeting ROS-mediated Akt/mTOR/FOXO1 pathway. Evid Based Complement Alternat Med 2018: 6049498, 2018. PMID: 30046342. DOI: 10.1155/2018/6049498
    OpenUrlCrossRefPubMed
  50. ↵
    1. Fu J,
    2. Zhu SH,
    3. Xu HB,
    4. Xu YQ,
    5. Wang X,
    6. Wang J and
    7. Kong PS
    : Xihuang pill potentiates the anti-tumor effects of temozolomide in glioblastoma xenografts through the Akt/mTOR-dependent pathway. J Ethnopharmacol 261: 113071, 2020. PMID: 32603676. DOI: 10.1016/j.jep.2020.113071
    OpenUrlCrossRefPubMed
  51. ↵
    1. Su L,
    2. Jiang Y,
    3. Xu Y,
    4. Li X,
    5. Gao W,
    6. Xu C,
    7. Zeng C,
    8. Song J,
    9. Weng W and
    10. Liang W
    : Xihuang pill promotes apoptosis of Treg cells in the tumor microenvironment in 4T1 mouse breast cancer by upregulating MEKK1/SEK1/JNK1/AP-1 pathway. Biomed Pharmacother 102: 1111-1119, 2018. PMID: 29710529. DOI: 10.1016/j.biopha.2018.03.063
    OpenUrlCrossRefPubMed
  52. ↵
    1. Xu X,
    2. Zhang J,
    3. Zhang Z,
    4. Wang M,
    5. Liu Y and
    6. Li X
    : Systems pharmacology in combination with proteomics reveals underlying mechanisms of Xihuang pill against triple-negative breast cancer. Bioengineered 11(1): 1170-1188, 2020. PMID: 33092442. DOI: 10.1080/21655979.2020.1834726
    OpenUrlCrossRefPubMed
  53. ↵
    1. Yang K,
    2. Zeng L,
    3. Ge A,
    4. Bao T,
    5. Xu T,
    6. Xie X and
    7. Liu L
    : Exploring the regulation mechanism of Xihuang pill, Olibanum and β-Boswellic acid on the biomolecular network of triple-negative breast cancer based on transcriptomics and chemical informatics methodology. Front Pharmacol 11: 825, 2020. PMID: 32595497. DOI: 10.3389/fphar.2020.00825
    OpenUrlCrossRefPubMed
  54. ↵
    1. Hsu LH,
    2. Chu NM and
    3. Kao SH
    : Estrogen, estrogen receptor and lung cancer. Int J Mol Sci 18(8): 1713, 2017. PMID: 28783064. DOI: 10.3390/ijms18081713
    OpenUrlCrossRefPubMed
  55. ↵
    1. Zhuang Z,
    2. Wang Y,
    3. Zhu R,
    4. Lin T,
    5. Zhang Y,
    6. Xie J and
    7. Liu Z
    : Exploring mechanisms of Xihuang Pill for anti-cancer based on network pharmacology. Traditional Chin Drug Res Clin Pharmacol 31: 823-831, 2020. Available at: https://chn.oversea.cnki.net/KCMS/detail/detail.aspx?dbcode=CJFD&dbname=CJFDLAST2020&filename=ZYXY202007013&v=FeKrVXSDumGEQ%25mmd2FemMXp%25mmd2FN6yMxrpbZO6TzG6SB5cO%25mmd2F8xuaROMpRzzbt3fsyuBXa96 [Last accessed on May 31, 2021]
    OpenUrl
  56. ↵
    1. Chen G and
    2. Goeddel DV
    : TNF-R1 signaling: a beautiful pathway. Science 296(5573): 1634-1635, 2002. PMID: 12040173. DOI: 10.1126/science.1071924
    OpenUrlAbstract/FREE Full Text
  57. ↵
    1. Liu W,
    2. Chen X,
    3. He Y,
    4. Tian Y,
    5. Xu L,
    6. Ma Y,
    7. Hu P,
    8. Su K,
    9. Luo Z,
    10. Wei L and
    11. Zhang J
    : TNF α inhibits xenograft tumor formation by A549 lung cancer cells in nude mice via the HIF 1α/VASP signaling pathway. Oncol Rep 41(4): 2418-2430, 2019. PMID: 30816548. DOI: 10.3892/or.2019.7026
    OpenUrlCrossRefPubMed
  58. ↵
    1. Yang Y,
    2. Lv SY,
    3. Ye W and
    4. Zhang L
    : Apelin/APJ system and cancer. Clin Chim Acta 457: 112-116, 2016. PMID: 27083318. DOI: 10.1016/j.cca.2016.04.001
    OpenUrlCrossRefPubMed
  59. ↵
    1. Uribesalgo I,
    2. Hoffmann D,
    3. Zhang Y,
    4. Kavirayani A,
    5. Lazovic J,
    6. Berta J,
    7. Novatchkova M,
    8. Pai TP,
    9. Wimmer RA,
    10. László V,
    11. Schramek D,
    12. Karim R,
    13. Tortola L,
    14. Deswal S,
    15. Haas L,
    16. Zuber J,
    17. Szűcs M,
    18. Kuba K,
    19. Dome B,
    20. Cao Y,
    21. Haubner BJ and
    22. Penninger JM
    : Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy. EMBO Mol Med 11(8): e9266, 2019. PMID: 31267692. DOI: 10.15252/emmm.201809266
    OpenUrlCrossRefPubMed
  60. ↵
    1. Kim TW,
    2. Hong DW,
    3. Kang CM and
    4. Hong SH
    : A novel PPARγ ligand, PPZ023, overcomes radioresistance via ER stress and cell death in human non-small-cell lung cancer cells. Exp Mol Med 52(10): 1730-1743, 2020. PMID: 33046822. DOI: 10.1038/s12276-020-00511-9
    OpenUrlCrossRefPubMed
    1. Chang WH and
    2. Lai AG
    : The pan-cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia. Ann NY Acad Sci 1448(1): 65-82, 2019. PMID: 31215667. DOI: 10.1111/nyas.14170
    OpenUrlCrossRefPubMed
  62. ↵
    1. Hazra S,
    2. Peebles KA,
    3. Sharma S,
    4. Mao JT and
    5. Dubinett SM
    : The role of PPARgamma in the cyclooxygenase pathway in lung cancer. PPAR Res 2008: 790568, 2008. PMID: 18769553. DOI: 10.1155/2008/790568
    OpenUrlCrossRefPubMed
  63. ↵
    1. Hu Z,
    2. Wang X,
    3. Yang Y,
    4. Zhao Y,
    5. Shen Z and
    6. Huang Y
    : MicroRNA expression profiling of lung adenocarcinoma in Xuanwei, China: A preliminary study. Medicine (Baltimore) 98(21): e15717, 2019. PMID: 31124951. DOI: 10.1097/MD.0000000000015717
    OpenUrlCrossRefPubMed
  64. ↵
    1. Wu M,
    2. Wu Y,
    3. Qian H,
    4. Tao Y,
    5. Pang J,
    6. Wang Y and
    7. Chen Y
    : Type II cGMP dependent protein kinase inhibits the migration, invasion and proliferation of several types of human cancer cells. Mol Med Rep 16(4): 5729-5737, 2017. PMID: 28849123. DOI: 10.3892/mmr.2017.7290
    OpenUrlCrossRefPubMed
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Traditional Chinese Medicine Xihuang Wan Inhibited Lewis Lung Carcinoma in a Syngeneic Model, Equivalent to Cytotoxic Chemotherapy, by Altering Multiple Signaling Pathways
ZHIYING ZHANG, JIANFENG WANG, HUA DUAN, DIANNA LIU, XIANGNAN ZHOU, XIMING LIN, HAOYUE PANG, MANQIANG SUN, TIAN ZHOU, ROBERT M. HOFFMAN, KAIWEN HU
In Vivo Jul 2021, 35 (4) 2005-2014; DOI: 10.21873/invivo.12469
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