Chinese Journal of Natural Medicines  2018, Vol. 16Issue (11): 801-810  DOI: 10.3724/SP.J.1009.2018.00801

Cite this article as: 

ZHOU Yu, CAO Han-Bo, LI Wen-Jun, ZHAO Li. The CXCL12 (SDF-1)/CXCR4 chemokine axis: Oncogenic properties, molecular targeting, and synthetic and natural product CXCR4 inhibitors for cancer therapy[J]. Chinese Journal of Natural Medicines, 2018, 16(11): 801-810.

Research funding

This work was supported by the National Natural Science Foundation of China (Nos. 81773774, 81473231, and 81673461), Science Foundation for Distinguished Young Scholars of Jiangsu Province (No. BK20150028), the National Science and Technology Major Project (No. 2017ZX09301014), the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. SKLNMZZCX201823), Program for Changjiang Scholars and Innovative Research Team in University (No. IRT1193), and the Open Project of State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine (No. TCMQ & E201704)

Corresponding author

ZHAO Li, Tel/Fax:86-25-83271055,

Article history

Received on: 17-Jun-2018
Available online: 20 December, 2018
The CXCL12 (SDF-1)/CXCR4 chemokine axis: Oncogenic properties, molecular targeting, and synthetic and natural product CXCR4 inhibitors for cancer therapy
ZHOU Yu1 , CAO Han-Bo2 , LI Wen-Jun2 , ZHAO Li2     
1 Center For Drug Evaluation, China Food and Drug Administration, Beijing 100022, China;
2 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China
[Abstract]: Chemokine 12 (CXCL12), also known as stromal cell derived factor-1 (SDF-1) and a member of the CXC chemokine subfamily, is ubiquitously expressed in many tissues and cell types. It interacts specifically with the ligand for the transmembrane G protein-coupled receptors CXCR4 and CXCR7. The CXCL12/CXCR4 axis takes part in a series of physiological, biochemical, and pathological process, such as inflammation and leukocyte trafficking, cancer-induced bone pain, and postsurgical pain, and also is a key factor in the cross-talking between tumor cells and their microenvironment. Aberrant overexpression of CXCR4 is critical for tumor survival, proliferation, angiogenesis, homing and metastasis. In this review, we summarized the role of CXCL12/CXCR4 in cancer, CXCR4 inhibitors under clinical study, and natural product CXCR4 antagonists. In conclusion, the CXCL12/CXCR4 signaling is important for tumor development and targeting the pathway might represent an effective approach to developing novel therapy in cancer treatment.
[Key words]: CXCL12/CXCR4     Tumor     Targeted therapy     Plerixafor    

Chemokines produced in distinct tissue microenvironments promote survival and migration of cancer cells. Chemokine (C-X-C motif) receptor 4 (CXCR4) is the most common chemokine receptor expressing in a variety of cancer cells. This receptor protein belonging to G protein-coupled cell surface receptors family [1]. Stromal cell-derived factor-1 (SDF-1, CXCL12), the ligand of CXCR4, is mainly secreted by marrow stromal cells in adults. CXCL12/CXCR4 signaling plays an important role in many physiological and pathological processes. For example, CXCL12/CXCR4 regulates epithelial-mesenchymal transition (EMT) in oral squamous cell carcinoma, glioblastoma, and sacral chondrosarcoma [2-4]. CXCR4 inhibition leads to suppression in angiogenesis and metastasis of sacral chondrosarcoma [5]. CXCL12/CXCR4 signaling also regulates adhesion to actin polymerization and vascular endothelium, as well as accommodate migration beneath and underneath bone mesenchymal stem cells (BMSCs) in leukemia cells [6]. In addition, CXCL12/CXCR4 axis is crucial for drug resistance in cancer cells [7]. Herein, we will review the effects of CXCL12/CXCR4 axis in cancer development and progression as well as the potential of targeting this pathway for cancer therapy.

Role of CXCL12/CXCR4 in Cancer Development CXCL12/CXCR4 regulates survival and proliferation of cancers

CXCL12/CXCR4 signaling plays an important role in proliferation of cancer cells. Joseph MD et al. have detected CXCR4 expression in pancreatic intraepithelial neoplasia (PanIN) tissues and demonstrated that CXCR4 could induce proliferation via activating Akt and ERK signaling in both murine and human pancreatic cancer cells [8]. As one of the most malignant and aggressive brain tumors, glioblastoma (GBM) has brought great harm to patients. In GBM, CXCL12/CXCR4 axis causes a significant increase in cell proliferation and survival, which can be reversed by blockage of CXCR4 [9]. Thompson et al. also have reported that CXCR4 mediates the proliferation of glioblastoma progenitor cells [10]. Barbieri et al. have highlighted that CXCL12/ CXCR4 interaction plays a pivotal role in meningioma cell proliferation via activating ERK1/2 pathway [11]. Down- regulation of CXCR4 significantly reduces the cell proliferation by inhibiting PI3K/AKT/NF-κB signaling pathway, and remarkably increases cell apoptosis in osteosarcoma cells [12]. A report has revealed that inhibition of CXCR4 and CXCR7 reduces the proliferation of human endometrial cancer and the targets could be useful for the treatment of the carcinoma [13]. In ovarian cancers, CXCL12/ CXCR4 signaling significantly promotes cancer proliferation, migration, invasion, and peritoneal metastasis [14]. It is safe to say that the Notch-targeted approach effectively prevents myeloma cell migration, proliferation and resistance to apoptosis by reducing CXCR4 and CXCL12 level [15]. Also, in uveal melanoma (UM), the signaling promotes UM cell proliferation and migration. Liu et al. have found the CXCR4-shRNA interfering vector specifically inhibits CXCR4 expression and the proliferation, adhesion, and migration of human breast cancer cells MDA-MB- 231 [16]. What's more, CXCR4 regulates cell proliferation and survival in laryngeal squamous carcinoma cells [17], human hilar cholangiocarcinoma [18], and human esophageal carcinoma cells [19]. Overall, CXCL12/CXCR4 axis is important for the survival and proliferation of various cancers.

CXCL12/CXCR4 regulates tumor angiogenesis

Among the factors involved in tumor angiogenesis, vascular endothelial growth factor (VEGF) is validated to be the closest one which can drive angiogenesis through binding with its natural receptor VEGFR2 [20-21]. VEGF expression has been found to be more pronounced in CXCR4 expressing cancer cells. CXCL12/CXCR4 signaling can increase VEGF-A promoter activity, promote angiogenesis, and enhance cancer cell viability [22]. Liang Z et al. have reported that CXCL12/ CXCR4 signaling axis induces angiogenesis and progression of cancers by increasing expression of VEGF through the activation of PI3K/Akt pathway [23]. CXCL12/CXCR4 induces secretion of VEGF in normal human megakaryoblasts in a PI3K/Akt/NF-κB dependent manner [24]. Claudio Napoli et al. have reported that CXCR4 plays a major role in neoangiogenesis to promote cancer progression, and inhibition of CXCR4/ "Yin Yang 1" (YY1) leads to impairing VEGF network and angiogenesis during malignancy [25]. In addition, hypoxia-inducible factor 1 (HIF-1) and VEGF may up-regulate CXCR4 in glioblastoma, which promotes tumor angiogenesis [26]. Also, VEGF up-regulates CXCL12 and CXCR4 mRNA expression, and contributes to U251 cell invasion [27].

Endothelial progenitor cells (EPCs) are pluripotent stem cells, which have the potential to differentiate into mature endothelial cells. They are very important in tumor angiogenesis. Recent evidence has demonstrated that the CXCL12 has a major role in the recruitment and retention of CXCR4+ Bone Marrow cells to the neo-angiogenic niches, resulting in revascularization of tumors. In addition, CXCR4 is expressed on EPCs, which can direct the cells migrate to tumors to induce angiogenesis [28]. CXCL12/CXCR4 signaling also inhibits apoptosis and induces proliferation of EPCs [29]. What's more, CXCL12/CXCR4 axis induces the differentiation, spouting, and tube formation of EPCs. Yu P et al. have reported that CXCL12/CXCR4/PI3K/p-Akt signaling pathway increases progesterone-induced EPC viability [30]. Also, adenosine increases the migration of EPCs via increasing the expression of CXCR4 [31]. Above all, CXCL12/CXCR4 signaling can promote tumor angiogenesis by increasing VEGF expression and influencing EPCs functions.

CXCL12/CXCR4 participates in cancer metastasis

Metastasis to main organs is the key cause of death among cancer patients and many factors are involved in cancer invasion, such as TGF-β, E-cadherin, and Wnt/β-catenin. The CXCL12/CXCR4 axis is also involved in metastasis of many human cancers. A previous study has shown that cancer cell invasion is reduced when CXCR4 neutralizing antibody is used or CXCR4 is knockdown [32], suggesting that CXCR4 expression is essential for cancer invasion. Kim et al. have detected the expression of CXCR4 in colorectal cancer patients with liver metastasis [33]. CXCR4 is also a chemokine receptor involved in the homing of metastatic breast cancer. It is highly expressed in breast cancer cells, contributing to cells tropism and invasion of the sites which secrete CXCL12, like lymph nodes, lungs, bone, and liver [34]. Yu T et al. have revealed that CXCR4 promotes Tca8113 migration and invasion by regulating MMP-9 and MMP-13 expression, perhaps via activation of the ERK signaling pathway [35]. In addition, PDZ-RhoGEF (PRG) regulates the migration and invasion of breast cancer cells in response to CXCL12, which is tightly correlated with the spatial regulation of Rho A activity [36]. Fontanella R et al. have shown that when cancer cells are treated with CXCR4 antagonist AMD3100, a reduction in their migration and invasion ability is observed [37]. Another study has shown that miR-494 suppresses the progression of breast cancer through Wnt/β-catenin signaling pathway, which is mediated by CXCR4 [38]. In a 3D microenvironment model, interstitial flow enhances cell motility, CXCR4 activation, and CXCL12-driven brain cancer invasion [39]. In summary, the chemokine CXCL12 and its receptor CXCR4 play a major role in cancer invasion and metastasis, indicating that CXCR4 may be the target for the treatment of metastatic cancers.

CXCL12/CXCR4 plays an important role in transformation of inflammatory carcinoma

Inflammation has been appropriately added to the list of hallmarks of cancer [40]. Pro-inflammatory cytokines are critical regulators of tumor microenvironment. They control proliferation of cancer cells and promote inflammation, tumor angiogenesis, and metastasis. Chemokines and their receptors are now known to play important roles in inflammation, infection, tissue injury, allergy, cardiovascular diseases, and malignant tumors [41]. A previous study has shown that IL-1β and IL-1R1 promote cancer growth and metastasis by up-regulating CXCR4 expression and that CXCR4 may be a link between inflammation and cancer [42]. Furthermore, HIF-2α that modulated macrophage migration by regulating the expression of the CXCR4 directly regulates pro-inflammatory cytokine/chemokine expression in macrophages activated in vitro [43]. Another study has revealed that CXCR4 antagonist significantly reduces local inflammation and significantly inhibits cancer cell growth, resulting in improved survival of the cancer-bearing mice [44]. So, CXCL12/CXCR4 may substantially improve cancer cell survival through promoting inflammation and tumor growth. In addition, resistin (an important player in inflammatory responses, and emerging as a mediator in inflammation-associated cancer) can upregulate the level of CXCL12, leading to activation of TLR4, p38 MARK, and NF-κB signaling pathway in gastric cancer cells [45]. Above all, in the tumor microenvironment, inflammatory cells and molecules influence almost every aspect of cancer progression and CXCL12/CXCR4 plays a critical role in the process.

CXCL12/CXCR4 is a key axis in tumor microenvironment

As described above, CXCL12/CXCR4 pathway regulates cancer cell proliferation, metastasis and angiogenesis. It also plays a key role in tumor microenvironment cross-talk in several solid tumors. As a G protein-coupled receptor, CXCR4 binds to its ligand CXCL12 to trigger different downstream signaling pathways in cancer cells and in cells of the surrounding microenvironment, which result in a variety of cellular responses including angiogenesis, metastasis, proliferation, and survival [46-47]. CXCL12/CXCR4 can promote the progression of cancers by directly enhancing cancer growth and by influencing tumor microenvironment, such as recruiting EPCs to cause tumor angiogenesis [48]. Also, carcinoma-associated fibroblasts can secret CXCL12, leading to cancer development in both paracrine and endocrine manner in the tumor microenvironment. In fact, CXCR4 is expressed in several cell types in the microenvironment, such as lymphocytes, hematopoietic stem cells, endothelial cells, and epithelial cells [47]. Hypoxic environment enhances CXCR4 expression through activation of HIF-1α in cancer cells and stromal cells, leading to further development of cancer [49]. So CXCR4 may be a target both in cancer cells and the surrounding stromal, providing a new strategy for efficient cancer therapy. Besides hypoxia, inflammatory cells and inflammatory factors in the tumor microenvironment can induce the expression of a variety of cytokines to promote cancer progression. A published study has evaluated the effect of inhibition of CXCR4 in xenograft mouse model of inflammatory breast cancer and the results show that inhibition of CXCR4 reduces primary tumor growth and metastasis [50]. Katoh H et al. have reported that the subsequent up-regulation of CXCL12/CXCR4 signaling facilitates cancer stromal formation by accelerating the recruitment of fibroblasts, resulting in cancer growth [51]. They have revealed that COX-2 and prostaglandin EP3/EP4 regulate the tumor stromal pro-angiogenic microenvironment via CXCL12/CXCR4 chemokine systems.

CXCL12/CXCR4 promotes development of hematologic malignancies

CXCR4 is normally expressed in T and B lymphocytes, monocytes, macrophages, neutrophils, and eosinophils. Pathological CXCR4 overexpression has been reported in hematopoietic malignancies such as leukemia and lymphoproliferative malignancies [52]. Bone marrow microenvironment plays critical roles in leukemogenesis, leukemia stem cell (LSC) survival, and drug resistance [53-55]. CXCL12/ CXCR4 axis is an important biological process for bone marrow microenvironment and is governed by a cascade of molecular interactions. The level of CXCR4 is significantly elevated in leukemic cells from patients with AML [56], and is closely related to poor prognosis [57-58]. CXCL12, which secreted from bone marrow cells, can induce CML cells to resist tyrosine kinase inhibitors (TKI) therapy from multiple aspects, such as the directional migration, adherence to marrow cavity, the mediation of cell protective dormancy, activation of numerous survival signaling pathways, the suppression of mitochondrial-dependent apoptosis and the up-regulated expression of BCL-6. In addition, AMD3100, an inhibitor of CXCR4, is known to block the CXCL12/CXCR4 interaction, disrupts the interaction between cancer and matrix, mobilizes the leukemia cells to keep away from the protective microenvironment [59]. In order to keep with the myeloma cells origin, the cells express high level CXCR4 and require stromal expression of CXCL12 for homing and niche maintenance, and AMD3100, clinically used for hematopoetic stem cells (HSCs) mobilization, has been proposed as an agent of inducing chemosensitivity in myeloma [60-61]. Nowadays, CXCR4-targeted endoradiotherapy (ERT) is a new theranostic approach, and CXCR4-directed ERT with Lu-Pentixather is distributed to leukemia harboring organs, resulting in an efficient reduction of leukemia [62].

CXCL12/CXCR4 Mediates Drug-resistance

High expression of CXCR12 is also important in drug- resistance in cancer therapy [63-65]. Hu et al. have reported that up-regulation of CXCR4 mediates Gefitinib-resistance in cross- talk with EMT in non-small cell lung cancer (NSCLC) [66]. CXCL12/CXCR4 axis also confers Adriamycin and Imatinib resistance in human chronic myelogenous leukemia in the BM microenvironment [65]. In pancreatic cancers, CXCL12/ CXCR4 axis also leads to the resistance to Gemcitabine [67]. In Gemcitabine-resistance PaCa cells, Gemcitabine induces the expression of CXCR4, but not in GEM-sensitive PaCa cells. This study has demonstrated that CXCL12/CXCR4 signaling really influences resistance to gemcitabine in PaCa cells [67]. Synthetic Exosome-Like Nanoparticles (SELN) can activate NF-κB, which regulates the expression and secretion of CXCL12. The interaction of CXCL12 and CXCR4 further activates Akt survival pathway to protect cells from death. So CXCL12/CXCR4 axis can promote the development of cancers, which has implications in drug resistance [68]. In bone marrow-disseminated cancer cells, with TGF-β2 being down- regulated, CXCL12/CXCR4 signaling is also inhibited. As a result, inhibition of CXCR4 reverses the drug resistance of BM-HEp3 cells. So, TGF-β2-triggered CXCL12/CXCR4 signaling is important for drug resistance [7]. In addition, ErbB-2-overexpressing cells become resistant to the anti- ErbB-2 agent Lapatinib by activating alternative mechanisms of controlling proliferation, such as Src and CXCR4 signaling. Blockade of CXCR4 represents a novel therapeutic intervention in Lapatinib-resistant breast cancer patients [69]. In Schultz's study [70], Tamoxifen-resistant cells have a higher percentage of cancer progenitor cells that are responsive to CXCR4 inhibition. Inhibition of CXCR4 or AhR with small molecule antagonists specifically target cancer stem-like cell populations in MCF7 cells and could be beneficial to the treatment of Tamoxifen-resistant breast cancer. In another study, drug-resistant colorectal cancer cells show an increased expression of CD133 and CXCR4. Lymph node stromal cells can secret CXCL12 which interacts with CXCR4 on colorectal cancer cells and then enhances drug-resistance [71]. Above all, CXCL12/CXCR4 signaling is critical for drug-resistance in cancers, which may be an important target for cancer therapy.

Considering other signaling pathways invovled in the biological effects of CXCL12/CXCR4, we compile the relevant pathways in Fig. 1.

Figure 1 CXCL12/CXCR4 related pathways
Anti-cancer Agents Targeted CXCL12/CXCR4 Axis Anti-cancer effects of synthetic drugs targeting CXCR4

As we know, chemokines and chemokine receptors regulate multiple physiological and pathological processes, such as morphogenesis, angiogenesis, immune responses and cancers. Among the multitudinous chemokine receptors, CXCR4 stands out for its pleiotropic roles. CXCR4 is expressed in at least 20 different human cancers, including cancer cells from brain neoplasm (neuronal and glial cancers) [72-73], neuroblastoma cells [74], colorectal cancer [71], prostate cancer [75], melanoma [76], breast cancer [77], ovarian cancer [78], and leukemia [56], among others. CXCL12, the ligand of CXCR4, is usually secreted in the tumor microenvironment by stromal cells and other cells. It can be combined with CXCR4 to active the downstream signaling pathway to promote cancer development. Therefore, it has been thought that CXCR4 antagonism could prevent the development of cancers by targeting multiple steps in the process. Here in we summarize the anti-cancer agents targeting CXCL12/CXCR4 axis, and the information on CXCR4 antagonists is listed in Table 1.

Table 1 Synthetic CXCR4 antagonists under clinical investigation

Plerixafor is the only drug currently used in the clinic. It was launched for NHL and MM patients in the US in December 2008 and launched in the EU August 2009. In January 2016, the drug was filed for Japanese approval for enhancing hematopoietic stem cell mobilization for autologous transplantation, blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). In the EU, the drug is indicated in combination with G-CSF to enhance mobilization of hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with lymphoma and MM whose cells mobilize poorly. Finally, plerixafor lacks CXCR4 specificity because it also binds the other CXCL12 receptor, CXCR7, as an allosteric agonist [79]. Recent studies have found that Plerixafor is also used in other treatments, such as promoting proliferation of Ewing sarcoma cell lines in vitro and activates receptor tyrosine kinase signaling [80] and mobilizing CD56 bright NK cells in blood, providing an allograft predicted to protect against GvHD [81].

A plurality of natural products' versatile use of CXCL12/ CXCR4

The anti-cancer activity of a large number of currently studied flavonoid compounds is also affected by the biological activity of CXCR4/CXCL12. Quercetin-3-O-glu- curonide, Quercetin, apigenin, Luteolin, Oroxylin A and Silymarin have anti-cancer effects through the inhibition of CXCR4 [65, 82-86]. Naringin, a major active ingredient in the Chinese herb Drynaria fortunei, can promote angiogenesis and inhibit endothelial cell apoptosis through the CXCL12/CXCR4/PI3K/Akt signaling pathway [87]. Puerarin, an isoflavone derivative, could significantly inhibit lipopolysaccharide (LPS)-induced MCF-7 and MDA-MB-231 cell migration, invasion and adhesion by regulating the expression of CCR7, MMP-2, MMP-9, ICAM, and CXCR4 [88]. IND02, a type A procyanidin polyphenol extracted from cinnamon, which is a bioflavonoid derivative that features trimeric and pentameric forms, displays an anti-HIV-1 activity against CXCR4 and CCR5 viruses [89]. Prenylated flavonoids glyceollins inhibit the function of EPCs in tumor neovascularization by inhibiting the mRNA expression of SDF-1 and CXCR4 [90]. Flavonoids, flavanones, isoflavones, bioketides, and prenylated flavonoids can produce anticancer and antiviral effects by modulating the SDF-1/CXCR4 axis.

In addition to the natural products of flavonoids, other natural products also have a regulatory effect on CXCR4. CXCR4 is deeply involved in several pathologies, such as HIV infection, rheumatoid arthritis, cancer development, progression, and metastasis. Nowadays, many natural products have been found to inhibit the biological axis of CXCL12/ CXCR4. Chen et al. have reported that Ginsenoside Rg3 regulates migration of a breast cancer cells by inhibiting CXCR4 expression at a dosage without obvious cytotoxicity [91]. Two chloroform extracts of Ficus deltoidea, FD1c and FD2c are able to inhibit cell migration and invasion by modulating the CXCL12-CXCR4 axis in human prostate cancer PC3 cells [92]. Penicillixanthone A (PXA), a natural xanthone dimer from jellyfish-derived fungus Aspergillus fumigates obtained from marine-derived, displays potent anti-HIV-1 activity by inhibiting infection against CCR5-tropic HIV-1 SF162 and CXCR4-tropic HIV-1 NL4-3 [93]. Urtica dioica extract can inhibit the ability of miR-21 to inhibit the proliferation and metastasis of breast cancer cells by down-regulating the expression of CXCR4 and other genes [94]. Methanolic extract of Boswellia serrate inhibits proliferation, angiogenesis, and migration and induces apoptosis in HT-29 cells by inhibiting of mPGES-1 and decreasing the CXCR4 level and its downstream targets [95]. "Yi Guan Jian" decoction may induce the differentiation of bone marrow mesenchymal stem cells (BMSCs) into hepatocyte-like cells (HLCs) to reverse dimethylnitrosamine-induced liver cirrhosis; this may be achieved via an upregulation of the SDF-1/CXCR4 axis to activate the mitogen activated protein kinase/ERK1/2 signaling pathway [96]. Treatment with Hormophysa triquerta polyphenol, an elixir, significantly inhibits the migration and invasion of pancreatic cancer cells induced by ionizing radiation by inhibiting the expression of CXCR4/COX-2, thus providing a new idea for drug treatment of treatment-resistant pancreatic cancer cells [97]. Pak et al. have reported that anticancer effects of herbal mixture extract in the pancreatic adenocarcinoma PANC1 cells are mediated by inhibiting the expression of apoptosis-associated genes (CXCR4, JAK2, and XIAP) and stem cell-associated genes (ABCG2, POU5F1, and SOX2) [98]. In summary, the anti-cancer activity of many natural products is achieved by inhibiting the CXCL12/ CXCR4 axis. Natural product CXCR4 antagonists under clinical investigation are summarized in Table 2.

Table 2 Natural product CXCR4 antagonists under clinical investigation

More and more investigations on the biological effects of the CXCL12/CXCR4 pathway have been reported in recent years, especially with increasing interests in its physiological role. Targeting the CXCL12/CXCR4 axis may have several beneficial effects, including affecting CXCR4-expressing primary cancer cells, synergizing with other cancer-targeted therapies and modulating the immune response. Blocking CXCL12/CXCR4 signaling may reduce cancer cell invasion and metastasis and inhibit cancer cell growth, which can provide a new idea for cancer treatment. By inhibiting CXCL12/ CXCR4, many natural medicines can achieve certain therapeutic effect as well. Surprisingly, newly reported results indicate that CXCL12 is able to promote the function of immune system [99-100], an inspiration for studying natural substances in the future. Natural compounds have nowadays attracted lots of interests among researchers. Thanks to their low toxicities and multi-targets in mechanisms of action, many natural medicines have little or no harm to normal cells and even protect them at the dose levels with inhibiting effects on cancer cell growth, providing more novel drug candidates for cancer therapy.

Loetscher M, Geiser T, O'Reilly T, et al. Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes[J]. J Biol Chem, 1994, 269(1): 232-237.
Duan Y, Zhang S, Wang L, et al. Targeted silencing of CXCR4 inhibits epithelial-mesenchymal transition in oral squamous cell carcinoma[J]. Oncol Lett, 2016, 12(3): 2055-2061. DOI:10.3892/ol.2016.4838
Yao CJ, Li PP, Song HS, et al. CXCL12/CXCR4 axis upregulates twist to induce EMT in human glioblastoma[J]. Mol Neurobiol, 2016, 53(6): 3948-3953. DOI:10.1007/s12035-015-9340-x
Yang P, Wang G, Huo HJ, et al. SDF-1/CXCR4 signaling up-regulates survivin to regulate human sacral chondrosarcoma cell cycle and epithelial-mesenchymal transition via ERK and PI3K/AKT pathway[J]. Med Oncol, 2015, 32: 377. DOI:10.1007/s12032-014-0377-x
Sun XJ, Charbonneau C, Wei L, et al. CXCR4-targeted therapy inhibits VEGF expression and chondrosarcoma angiogenesis and metastasis[J]. Mol Cancer Ther, 2013, 12(7): 1163-1170. DOI:10.1158/1535-7163.MCT-12-1092
Möhle R, Failenschmid C, Bautz F, et al. Overexpression of the chemokine receptor CXCR4 in B cell chronic lymphocytic leukemia is associated with increased functional response to stromal cell-derived factor-1 (SDF-1)[J]. Leukemia, 1999, 13(12): 1954-1959. DOI:10.1038/sj.leu.2401602
Nakamura T, Shinriki S, Jono H, et al. Intrinsic TGF-beta2- triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance and a slow-cycling state in bone marrow-dis- seminated tumor cells[J]. Oncotarget, 2015, 6(2): 1008-1019.
Shen X, Artinyan A, Jackson D, et al. Chemokine receptor CXCR4 enhances proliferation in pancreatic cancer cells through AKT and ERK dependent pathways[J]. Pancreas, 2010, 39(1): 81-87. DOI:10.1097/MPA.0b013e3181bb2ab7
do Carmo A, Patricio I, Cruz MT, et al. CXCL12/CXCR4 promotes motility and proliferation of glioma cells[J]. Cancer Biol Ther, 2010, 9(1): 56-65. DOI:10.4161/cbt.9.1.10342
Ehtesham M, Mapara KY, Stevenson CB, et al. CXCR4 mediates the proliferation of glioblastoma progenitor cells[J]. Cancer Lett, 2009, 274(2): 305-312. DOI:10.1016/j.canlet.2008.09.034
Barbieri F, Bajetto A, Porcile C, et al. CXC receptor and chemokine expression in human meningioma: SDF1/CXCR4 signaling activates ERK1/2 and stimulates meningioma cell proliferation[J]. Ann NY Acad Sci, 2006, 1090: 332-343. DOI:10.1196/annals.1378.037
Jiang C, Ma S, Hu R, et al. Effect of CXCR4 on apoptosis in osteosarcoma cells via the PI3K/Akt/NF-kappabeta signaling pathway[J]. Cell Physiol Biochem, 2018, 46(6): 2250-2260. DOI:10.1159/000489593
Long P, Sun FY, Ma YY, et al. Inhibition of CXCR4 and CXCR7 for reduction of cell proliferation and invasion in human endometrial cancer[J]. Tumour Biol, 2016, 37(6): 7473-7480. DOI:10.1007/s13277-015-4580-y
Guo Q, Gao BL, Zhang XJ, et al. CXCL12-CXCR4 axis promotes proliferation, migration, invasion, and metastasis of ovarian cancer[J]. Oncol Res, 2014, 22(5-6): 247-258.
Mirandola L, Apicella L, Colombo M, et al. Anti-Notch treatment prevents multiple myeloma cells localization to the bone marrow via the chemokine system CXCR4/SDF-1[J]. Leukemia, 2013, 27(7): 1558-1566. DOI:10.1038/leu.2013.27
Guo SY, Xiao D, Liu YH, et al. Interfering with CXCR4 expression inhibits proliferation, adhesion and migration of breast cancer MDA-MB-231 cells [J]. Oncol Lett, 2014, 8(4): 1557-1562. DOI:10.3892/ol.2014.2323
Luo HN, Wang ZH, Sheng Y, et al. MiR-139 targets CXCR4 and inhibits the proliferation and metastasis of laryngeal squamous carcinoma cells[J]. Med Oncol, 2014, 31(1): 789. DOI:10.1007/s12032-013-0789-z
Tan XY, Chang S, Liu W, et al. Silencing of CXCR4 inhibits tumor cell proliferation and neural invasion in human hilar cholangiocarcinoma[J]. Gut Liver, 2014, 8(2): 196-204. DOI:10.5009/gnl.2014.8.2.196
Wang DF, Lou N, Qiu MZ, et al. Effects of CXCR4 gene silencing by lentivirus shRNA on proliferation of the EC9706 human esophageal carcinoma cell line[J]. Tumour Biol, 2013, 34(5): 2951-2959. DOI:10.1007/s13277-013-0858-0
Choi HS, Lee K, Kim MK, et al. DSGOST inhibits tumor growth by blocking VEGF/VEGFR2-activated angiogenesis[J]. Oncotarget, 2016, 21(6): 21775-21785.
Ribatti D. Tumor refractoriness to anti-VEGF therapy[J]. Oncotarget, 2016, 7(29): 46668-46677.
Pages G, Pouyssegur J. Transcriptional regulation of the vascular endothelial growth factor gene—a concert of activating factors[J]. Cardiovasc Res, 2005, 65(3): 564-573. DOI:10.1016/j.cardiores.2004.09.032
Liang Z, Brooks J, Willard M, et al. CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway[J]. Biochem Biophys Res Commun, 2007, 359(3): 716-722. DOI:10.1016/j.bbrc.2007.05.182
Majka M, Janowska-Wieczorek A, Ratajczak J, et al. Stromal-derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis[J]. Blood, 2000, 96(13): 4142-4151.
de Nigris F, Crudele V, Giovane A, et al. CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy[J]. Proc Natl Acad Sci USA, 2010, 107(32): 14484-14489. DOI:10.1073/pnas.1008256107
Zagzag D, Lukyanov Y, Lan L, et al. Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion[J]. Lab Invest, 2006, 86(12): 1221-1232. DOI:10.1038/labinvest.3700482
Hong X, Jiang F, Kalkanis SN, et al. SDF-1 and CXCR4 are up-regulated by VEGF and contribute to glioma cell invasion[J]. Cancer Lett, 2006, 236(1): 39-45. DOI:10.1016/j.canlet.2005.05.011
Qin G, Chen YQ, Li HD, et al. Melittin inhibits tumor angiogenesis modulated by endothelial progenitor cells associated with the SDF-1 alpha/CXCR4 signaling pathway in a UMR-106 osteosarcoma xenograft mouse model[J]. Mol Med Rep, 2016, 14(1): 57-68. DOI:10.3892/mmr.2016.5215
Zheng H, Dai T, Zhou BQ, et al. SDF-1alpha/CXCR4 decreases endothelial progenitor cells apoptosis under serum deprivation by PI3K/Akt/eNOS pathway[J]. Atherosclerosis, 2008, 201(1): 36-42. DOI:10.1016/j.atherosclerosis.2008.02.011
Yu P, Zhang ZF, Li SJ, et al. Progesterone modulates endo- thelial progenitor cell (EPC) viability through the CXCL12/ CXCR4/PI3K/Akt signalling pathway[J]. Cell Prolif, 2016, 49(1): 48-57. DOI:10.1111/cpr.2016.49.issue-1
Rolland-Turner M, Goretti E, Bousquenaud M, et al. Adenosine stimulates the migration of human endothelial progenitor cells. Role of CXCR4 and microRNA-150[J]. PLoS One, 2013, 8(1): e54135. DOI:10.1371/journal.pone.0054135
Krohn A, Song YH, Muehlberg F, et al. CXCR4 receptor positive spheroid forming cells are responsible for tumor invasion in vitro[J]. Cancer Lett, 2009, 280(1): 65-71. DOI:10.1016/j.canlet.2009.02.005
Kim J, Mori T, Chen SL, et al. Chemokine receptor CXCR4 expression in patients with melanoma and colorectal cancer liver metastases and the association with disease outcome[J]. Ann Surg, 2006, 244(1): 113-120. DOI:10.1097/01.sla.0000217690.65909.9c
Maroni P, Bendinelli P, Matteucci E, et al. HGF induces CXCR4 and CXCL12-mediated tumor invasion through Ets1 and NF-kappaB[J]. Carcinogenesis, 2007, 28(2): 267-279.
Yu T, Wu Y, Helman JI, et al. CXCR4 promotes oral squamous cell carcinoma migration and invasion through inducing expression of MMP-9 and MMP-13 via the ERK signaling pathway[J]. Mol Cancer Res, 2011, 9(2): 161-172. DOI:10.1158/1541-7786.MCR-10-0386
Struckhoff AP1, Rana MK, Kher SS, et al. PDZ-RhoGEF is essential for CXCR4- driven breast tumor cell motility through spatial regulation of RhoA[J]. J Cell Sci, 2013, 126(Pt 19): 4514-4526.
Fontanella R, Pelagalli A, Nardelli A, et al. A novel antagonist of CXCR4 prevents bone marrow-derived mesenchymal stem cell-mediated osteosarcoma and hepatocellular carcinoma cell migration and invasion[J]. Cancer Lett, 2016, 370(1): 100-107. DOI:10.1016/j.canlet.2015.10.018
Shen PF, Chen XQ, Liao YC, et al. miR-494 suppresses the progression of breast cancer in vitro by targeting CXCR4 through the Wnt/beta-catenin signaling pathway[J]. Oncol Rep, 2015, 34(1): 525-531. DOI:10.3892/or.2015.3965
Munson JM, Bellamkonda RV, Swartz MA. Interstitial flow in a 3D microenvironment increases glioma invasion by a CXCR4-dependent mechanism[J]. Cancer Res, 2013, 73(5): 1536-1546. DOI:10.1158/0008-5472.CAN-12-2838
Qin HJ, Zhang ZY, Liu MH, et al. Efficient assimilation of cyanobacterial nitrogen by water hyacinth[J]. Bioresour Technol, 2017, 241: 1197-1200. DOI:10.1016/j.biortech.2017.06.104
Luo XB, Xu L, Liang DY, et al. Comparative transcriptomics uncovers alternative splicing and molecular marker development in radish (Raphanus sativus L.)[J]. BMC Genomics, 2017, 18(1): 505. DOI:10.1186/s12864-017-3874-4
Zheng YX, Wang YL, Pan J, et al. Semi-continuous production of high-activity pectinases by immobilized Rhizopus oryzae using tobacco wastewater as substrate and their utilization in the hydrolysis of pectin-containing lignocellulosic biomass at high solid content[J]. Bioresour Technol, 2017, 241: 1138-1144. DOI:10.1016/j.biortech.2017.06.066
Zhang YC, Jin GM, Cao QZ, et al. Distribution of axial length in Chinese congenital ectopia lentis patients: a retrospective study[J]. BMC Ophthalmol, 2017, 17: 113. DOI:10.1186/s12886-017-0508-1
Mao AW, Jiang TH, Sun XJ, et al. Application of chemokine receptor antagonist with stents reduces local inflammation and suppresses cancer growth[J]. Tumour Biol, 2015, 36(11): 8637-8643. DOI:10.1007/s13277-015-3557-1
Deng YP, Liu YJ, Yang ZQ, et al. Human bocavirus induces apoptosis and autophagy in human bronchial epithelial cells[J]. Exp Ther Med, 2017, 14(1): 753-758. DOI:10.3892/etm.2017.4533
Gagliardi F, Narayanan A, Reni M, et al. The role of CXCR4 in highly malignant human gliomas biology: current knowledge and future directions[J]. Glia, 2014, 62(7): 1015-1023. DOI:10.1002/glia.22669
Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment[J]. Blood, 2006, 107(5): 1761-1767. DOI:10.1182/blood-2005-08-3182
Cappellari R, D'Anna M, Avogaro A, et al. Plerixafor improves the endothelial health balance. The effect of diabetes analysed by polychromatic flow cytometry[J]. Atherosclerosis, 2016, 251: 373-380. DOI:10.1016/j.atherosclerosis.2016.05.028
Wu XL, Lin H, Chen SJ, et al. Development and application of a reverse transcriptase droplet digital PCR (RT-ddPCR) for sensitive and rapid detection of Japanese encephalitis virus[J]. J Virol Methods, 2017, 248: 166-171. DOI:10.1016/j.jviromet.2017.06.015
Singh B, Cook KR, Martin C, et al. Evaluation of a CXCR4 antagonist in a xenograft mouse model of inflammatory breast cancer[J]. Clin Exp Metastasis, 2010, 27(4): 233-240. DOI:10.1007/s10585-010-9321-4
Katoh H, Hosono K, Ito Y, et al. COX-2 and prostaglandin EP3/EP4 signaling regulate the tumor stromal proangiogenic microenvironment via CXCL12-CXCR4 chemokine systems[J]. Am J Pathol, 2010, 176(3): 1469-1483. DOI:10.2353/ajpath.2010.090607
Wester HJ, Keller U, Schottelius M, et al. Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging[J]. Theranostics, 2015, 5(6): 618-630. DOI:10.7150/thno.11251
Zeng Z, Shi YX, Samudio IJ, et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML[J]. Blood, 2009, 113(24): 6215-6224. DOI:10.1182/blood-2008-05-158311
Tabe Y, Shi YX, Zeng Z, et al. TGF-beta-neutralizing antibody 1D11 enhances cytarabine-induced apoptosis in AML cells in the bone marrow microenvironment[J]. PLoS One, 2013, 8(6): e62785. DOI:10.1371/journal.pone.0062785
Sison EA, McIntyre E, Magoon D, et al. Dynamic chemotherapy-induced upregulation of CXCR4 expression: a mechanism of therapeutic resistance in pediatric AML[J]. Mol Cancer Res, 2013, 11(9): 1004-1016. DOI:10.1158/1541-7786.MCR-13-0114
Herhaus P, Habringer S, Philipp-Abbrederis K, et al. Targeted positron emission tomography imaging of CXCR4 expression in patients with acute myeloid leukemia[J]. Haematologica, 2016, 101(8): 932-940. DOI:10.3324/haematol.2016.142976
Mannelli F, Cutini I, Gianfaldoni G, et al. CXCR4 expression accounts for clinical phenotype and outcome in acute myeloid leukemia[J]. Cytometry B Clin Cytom, 2014, 86(5): 340-349. DOI:10.1002/cytob.21156
Wang Y, Xie Q, Liang CL, et al. Chinese medicine Ginseng and Astragalus granules ameliorate autoimmune diabetes by upregulating both CD4 + FoxP3 + and CD8 + CD122 + PD1 + regulatory T cells[J]. Oncotarget, 2017, 8(36): 60201-60209.
Guest EM, Aplenc R, Sung L, et al. Gemtuzumab ozogamicin in infants with AML: results from the Children's oncology group trials, AAML03P1 and AAML0531[J]. Blood, 2017, 130(7): 943-945. DOI:10.1182/blood-2017-01-762336
Liu T, Zhang H, Sun L, et al. FSIP1 binds HER2 directly to regulate breast cancer growth and invasiveness[J]. Proc Natl Acad Sci USA, 2017, 114(29): 7683-7688. DOI:10.1073/pnas.1621486114
Chen M, Wang YZ, Ma CC, et al. Empathy skill-dependent modulation of working memory by painful scene[J]. Sci Rep, 2017, 7(1): 4527. DOI:10.1038/s41598-017-04702-9
Habringer S, Lapa C, Herhaus P, et al. Dual targeting of acute leukemia and supporting niche by CXCR4-directed theranostics[J]. Theranostics, 2018, 8(2): 369-383. DOI:10.7150/thno.21397
Zhang X, Liu Y, Lu L, et al. Oroxyloside A overcomes bone marrow microenvironment-mediated chronic myelogenous leukemia resistance to imatinib via suppressing hedgehog pathway[J]. Front Pharmacol, 2017, 8: 526. DOI:10.3389/fphar.2017.00526
Li WJ, Ding QL, Ding YX, et al. Oroxylin A reverses the drug resistance of chronic myelogenous leukemia cells to imatinib through CXCL12/CXCR7 axis in bone marrow microenvironment[J]. Mol Carcinog, 2017, 56(3): 863-876. DOI:10.1002/mc.v56.3
Wang Y, Miao HC, Li W, et al. CXCL12/CXCR4 axis confers adriamycin resistance to human chronic myelogenous leukemia and oroxylin A improves the sensitivity of K562/ADM cells[J]. Biochem Pharmacol, 2014, 90(3): 212-225. DOI:10.1016/j.bcp.2014.05.007
Hu Y, Zang JL, Qin XB, et al. Epithelial-to-mesenchymal transition correlates with gefitinib resistance in NSCLC cells and the liver X receptor ligand GW3965 reverses gefitinib resistance through inhibition of vimentin[J]. Onco Targets Ther, 2017, 10: 2341-2348. DOI:10.2147/OTT
Morimoto M, Matsuo Y, Koide S, et al. Enhancement of the CXCL12/CXCR4 axis due to acquisition of gemcitabine resistance in pancreatic cancer: effect of CXCR4 antagonists[J]. BMC Cancer, 2016, 16: 305. DOI:10.1186/s12885-016-2340-z
Beloribi-Djefaflia S, Siret C, Lombardo D. Exosomal lipids induce human pancreatic tumoral MiaPaCa-2 cells resistance through the CXCR4-SDF-1alpha signaling axis[J]. Oncoscience, 2015, 2(1): 15-30.
De Luca A, D'Alessio A, Gallo M, et al. Src and CXCR4 are involved in the invasiveness of breast cancer cells with acquired resistance to lapatinib[J]. Cell Cycle, 2014, 13(1): 148-156. DOI:10.4161/cc.26899
Dubrovska A, Hartung A, Bouchez LC, et al. CXCR4 activation maintains a stem cell population in tamoxifen- resistant breast cancer cells through AhR signalling [J]. Br J Cancer, 2012, 107(1): 43-52. DOI:10.1038/bjc.2012.105
Margolin DA, Silinsky J, Grimes C, et al. Lymph node stromal cells enhance drug- resistant colon cancer cell tumor formation through SDF-1alpha/CXCR4 paracrine signaling[J]. Neoplasia, 2011, 13(9): 874-886. DOI:10.1593/neo.11324
Larsen PH, Hao C, Yong VW. CXCR4 is a major chemokine receptor on glioma cells and mediates their survival[J]. J Biol Chem, 2002, 277(51): 49481-49487. DOI:10.1074/jbc.M206222200
Rubin JB, Kung AL, Klein RS, et al. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors[J]. Proc Natl Acad Sci USA, 2003, 100(23): 13513-13518. DOI:10.1073/pnas.2235846100
Geminder H, Sagi-Assif O, Goldberg L, et al. A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell- derived factor-1, in the development of bone marrow metastases in neuroblastoma [J]. J Immunol, 2001, 167(8): 4747-4757. DOI:10.4049/jimmunol.167.8.4747
Wang JH, Wang JC, Sun YX, et al. Diverse signaling pathways through the SDF-1/CXCR4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis[J]. Cell Signal, 2005, 17(12): 1578-1592. DOI:10.1016/j.cellsig.2005.03.022
Scala S, Ottaiano A, Ascierto PA, et al. Expression of CXCR4 predicts poor prognosis in patients with malignant melanoma[J]. Clin Cancer Res, 2005, 11(5): 1835-1841. DOI:10.1158/1078-0432.CCR-04-1887
Rovito D, Gionfriddo G, Barone I, et al. Ligand-activated PPAR gamma downregulates CXCR4 gene expression through a novel identified PPAR response element and inhibits breast cancer progression[J]. Oncotarget, 2016, 7(40): 65109-65124.
Scotton CJ, Wilson JL, Scott K, et al. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer[J]. Cancer Res, 2002, 62(20): 5930-5938.
Kalatskaya I, Berchiche YA, Gravel S, et al. AMD3100 is a CXCR7 ligand with allosteric agonist properties[J]. Mol Pharmacol, 2009, 75(5): 1240-1247. DOI:10.1124/mol.108.053389
Berning P, Schaefer C, Clemens D, et al. The CXCR4 antagonist plerixafor (AMD3100) promotes proliferation of Ewing sarcoma cell lines in vitro and activates receptor tyrosine kinase signaling[J]. Cell Commun Signal, 2018, 16(1): 21. DOI:10.1186/s12964-018-0233-2
Wong PPC, Kariminia A, Jones D, et al. Plerixafor effectively mobilizes CD56 (bright) NK cells in blood providing an allograft predicted to protect against GvHD[J]. Blood, 2018, 131(25): 2863-2866. DOI:10.1182/blood-2018-03-836700
Baral S, Pariyar R, Kim J, et al. Quercetin-3-O-glucuronide promotes the proliferation and migration of neural stem cells[J]. Neurobiol Aging, 2017, 52: 39-52. DOI:10.1016/j.neurobiolaging.2016.12.024
He YZ, Cao XP, Liu XS, et al. Quercetin reverses experimental pulmonary arterial hypertension by modulating the TrkA pathway[J]. Exp Cell Res, 2015, 339(1): 122-134. DOI:10.1016/j.yexcr.2015.10.013
Li X, Han YP, Zhou QY, et al. Apigenin, a potent suppressor of dendritic cell maturation and migration, protects against collagen-induced arthritis[J]. J Cell Mol Med, 2016, 20(1): 170-180. DOI:10.1111/jcmm.12717
Wang Y, Liang WC, Pan WL, et al. Silibinin, a novel chemokine receptor type 4 antagonist, inhibits chemokine ligand 12-induced migration in breast cancer cells[J]. Phytomedicine, 2014, 21(11): 1310-1317. DOI:10.1016/j.phymed.2014.06.018
Wang L, Li W, Lin M, et al. Luteolin, ellagic acid and punicic acid are natural products that inhibit prostate cancer metastasis[J]. Carcinogenesis, 2014, 35(10): 2321-2330. DOI:10.1093/carcin/bgu145
Zhao Z, Ma X, Ma J, et al. Naringin enhances endothelial progenitor cell (EPC) proliferation and tube formation capacity through the CXCL12/CXCR4/PI3K/Akt signaling pathway[J]. Chem Biol Interact, 2018, 286: 45-51. DOI:10.1016/j.cbi.2018.03.002
Liu XX, Zhao W, Wang W, et al. Puerarin suppresses LPS-induced breast cancer cell migration, invasion and adhesion by blockage NF-kappaB and Erk pathway[J]. Biomed Pharmacother, 2017, 92: 429-436. DOI:10.1016/j.biopha.2017.05.102
Connell BJ, Chang SY, Prakash E, et al. A cinnamon-derived procyanidin compound displays anti-HIV-1 activity by blocking heparan sulfate- and co-receptor-binding sites on gp120 and reverses T cell exhaustion via impeding Tim-3 and PD-1 upregulation[J]. PLoS One, 2016, 11(10): e0165386. DOI:10.1371/journal.pone.0165386
Choi JH, Nguyen MP, Jung SY, et al. Inhibitory effect of glyceollins on vasculogenesis through suppression of endothelial progenitor cell function[J]. Mol Nutr Food Res, 2013, 57(10): 1762-1771.
Chen XP, Qian LL, Jiang H, et al. Ginsenoside Rg3 inhibits CXCR4 expression and related migrations in a breast cancer cell line[J]. Int J Clin Oncol, 2011, 16(5): 519-523. DOI:10.1007/s10147-011-0222-6
Hanafi MMM, Afzan A, Yaakob H, et al. In vitro pro-apoptotic and anti-migratory effects of Ficus deltoidea L. plant extracts on the human prostate cancer cell lines PC3[J]. Front Pharmacol, 2017, 8: 895. DOI:10.3389/fphar.2017.00895
Tan SY, Yang B, Liu J, et al. Penicillixanthone A, a marine-derived dual-coreceptor antagonist as anti-HIV-1 agent[J]. Nat Prod Res, 2017, 114(29): 7683-7688.
Mansoori B, Mohammadi A, Hashemzadeh S, et al. Urtica dioica extract suppresses miR-21 and metastasis-related genes in breast cancer[J]. Biomed Pharmacother, 2017, 93: 95-102. DOI:10.1016/j.biopha.2017.06.021
Ranjbarnejad T, Saidijam M, Moradkhani S, et al. Methanolic extract of Boswellia serrata exhibits anti-cancer activities by targeting microsomal prostaglandin E synthase-1 in human colon cancer cells[J]. Prostaglandins Other Lipid Mediat, 2017, 131: 1-8. DOI:10.1016/j.prostaglandins.2017.05.003
Xiang Y, Pang BY, Zhang Y, et al. Effect of Yi Guan Jian decoction on differentiation of bone marrow mesenchymalstem cells into hepatocyte-like cells in dimethylnitrosamine-induced liver cirrhosis in mice[J]. Mol Med Rep, 2017, 15(2): 613-626. DOI:10.3892/mmr.2016.6083
Aravindan S, Ramraj S, Kandasamy K, et al. Hormophysa triquerta polyphenol, an elixir that deters CXCR4- and COX2-dependent dissemination destiny of treatment-resistant pancreatic cancer cells[J]. Oncotarget, 2017, 8(4): 5717-5734.
Pak PJ, Kang BH, Park SH, et al. Antitumor effects of herbal mixture extract in the pancreatic adenocarcinoma cell line PANC1[J]. Oncol Rep, 2016, 36(5): 2875-2883. DOI:10.3892/or.2016.5067
Garg B, Giri B, Modi S, et al. NFkappaB in pancreatic stellate cells reduces infiltration of tumors by cytotoxic T cells and killing of cancer cells, via upregulation of CXCL12[J]. Gastroenterology, 2018, 155(3): 880-891. DOI:10.1053/j.gastro.2018.05.051
Li BH, Wang Z, Wu H, et al. Epigenetic regulation of CXCL12 plays a critical role in mediating tumor progression and the immune response in osteosarcoma[J]. Cancer Res, 2018, 78(14): 3938. DOI:10.1158/0008-5472.CAN-17-3801