Open Access

BRM270 targets cancer stem cells and augments chemo‑sensitivity in cancer (Review)

  • Authors:
    • Nisansala Chandimali
    • Hyebin Koh
    • Jihwan Kim
    • Jaihyung Lee
    • Yang Ho Park
    • Hu-Nan Sun
    • Taeho Kwon
  • View Affiliations

  • Published online on: August 7, 2020     https://doi.org/10.3892/ol.2020.11964
  • Article Number: 103
  • Copyright: © Chandimali et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Over the past decade, a number of studies have demonstrated the resistance of cancer cells to conventional drugs and have recognized this as a major challenge in cancer therapy. While attempting to understand the underlying mechanisms of chemoresistance, several studies have suggested that the presence of cancer stem cells (CSCs) in tumors is one of the major pathways contributing toward resistance. Chemoresistance leads to cancer treatment failure and worsens the prognosis of patients. Natural herbal compounds are gaining attention as an alternative treatment strategy for cancer. These compounds may be effective against chemoresistant cells either alone or synergistically alongside conventional drugs, sensitizing cancer cells and enhancing the therapeutic efficacy. BRM270 is a natural compound made from seven herbal plant (Saururus chinensis, Citrus unshiu Markovich, Aloe vera, Arnebia euchroma, Portulaca oleracea, Prunella vulgaris var. lilacina and Scutellaria bacicalensis) extracts used in Asian traditional medicine and has the potential to target CSCs. Several studies have demonstrated the positive effects of BRM270 against chemoresistant cancer and its synergy alongside existing cancer drugs, including paclitaxel and gefitinib. These effects have been observed against various cancer types, including resistant non‑small cell lung cancer (NSCLC), glioblastoma, multi‑drug resistant osteosarcoma, cervical cancer, pancreatic cancer and hepatocarcinoma. The present review discusses the effects of BRM270 treatment against CSC‑associated chemoresistance in common types of cancer.

Introduction

Emergence of primary and acquired resistance to existing conventional chemotherapies is one of the major challenges to overcome in the clinical management of cancer (1,2). Patients with chemoresistant cancer do not respond to conventional drugs, which results in a poor prognosis and is often associated with the reoccurrence of malignancies following treatment (3,4). Therefore, understanding the underlying molecular mechanisms of chemoresistance is necessary to improve the survival of these patients. The cancer stem cell (CSC) phenotype is one of the favored molecular mechanisms of chemoresistance (1). However, eradication of CSC populations to increase the therapeutic response of cancer cells to existing chemotherapies remains a challenge (5). Therefore, novel strategies to eliminate CSC populations and overcome chemoresistance are key for the successful clinical treatment of certain cancer types.

Herbal remedies have been used in traditional Asian medicine for centuries to treat various diseases. Recently, they have attracted global attention as potential strategies for overcoming the chemoresistance of cancer cells, without any observable side effects (1,6). Medicinal plant extracts have the potential to treat human cancer either alone or synergistically with existing chemotherapeutic drugs to inhibit resistance (711). BRM270 (BRMLife) is a formulated extraction from seven medicinal plants used in Asian medicine, including Saururus chinensis, Citrus unshiu Markovich, Aloe vera, Arnebia euchroma, Portulaca oleracea, Prunella vulgaris var. lilacina and Scutellaria bacicalensis (Fig. 1) (1). Recently, the effectiveness of BRM270 was demonstrated as an alternative treatment to chemotherapy on non-small cell lung cancer (NSCLC) stem cells, which were resistant to EGFR-TKIs (epidermal growth receptor-specific tyrosine kinase inhibitors) (1). Similarly, previous studies have reported that BRM270 has the potential to downregulate tumorigenesis via the following mechanisms: Suppression of NF-κB signaling in multidrug resistance (MDR)-induced stem-like cells, inhibition of cervical CSC proliferation via SOX2 restriction, suppression of the recurrence and stem cell properties of glioblastoma, suppression of pancreatic CSC proliferation, and prevention of inflammation-promoted hepatocarcinogenesis (1214).

Previous studies have also demonstrated the individual effects of the seven plant extract constituents of BRM270 (1518). The present review discusses our current understanding of the individual and synergistic effects of BRM270 and highlights the important role of this compound in disrupting the CSC phenotype and overcoming the chemoresistance of cancer.

BRM270 overcomes chemoresistance by targeting cancer stem cells

BRM270 targets EGFR-TKI-resistant NSCLC stem cells

NSCLC includes adenocarcinomas, squamous cell carcinomas and large-cell carcinomas, accounting for ~85% of all lung cancer cases (19,20). The main treatment strategies for NSCLC are chemotherapy and radiotherapy, which fail to improve the survival rates of patients owing to primary and acquired resistance; therefore, only 15% of patients with NSCLC have a 5-year survival rate (21,22). Inhibition of the EGFR tyrosine kinase pathway decreases NSCLC tumorigenesis, and EGFR-TKIs, including gefitinib and paclitaxel, are first-line treatments (1). However, the majority of patients with initial responses to EGFR-TKI treatment become resistant after 10–16 months (1). Resistance to the first generation of EGFR-TKIs has led to the development of novel drug generations and combination therapies (1,22,23).

Due to the high resistance of NSCLCs to EGFR-TKIs, studies aiming to understand the mechanisms of resistance and to identify potential anti-resistance approaches remain necessary. Our recent study suggested a safe and effective alternative treatment involving the use of BRM270 for patients with EGFR-TKI-resistant NSCLC (1). The therapeutic efficacy of BRM270 against both non-resistant and EGFR-TKI-resistant lung adenocarcinoma cells was demonstrated (1). Resistance was derived from repeated exposure of lung adenocarcinoma cells to gefitinib and paclitaxel (1). It was demonstrated that BRM270 induced the apoptosis of chemoresistant NSCLC cells and caused G2/M cell cycle arrest via the inhibition of NF-κB/Bcl2 signaling, thereby suppressing cell proliferation. Furthermore, it was demonstrated that BRM270 was capable of suppressing chemoresistant NSCLC stem cells by inhibiting epithelial-mesenchymal transition (EMT), metastasis and stemness (1). BRM270 was also reported to induce the expression of microRNA-128 (miR-128) in chemoresistant NSCLC (1). MicroRNA (miR)-128 is considered a tumor suppressor in various types of cancer (2426), and acts against NSCLC cells by directly regulating vascular endothelial growth factor C (VEGF-C) (27). MiR-128 also induces lung cancer cell apoptosis by directly targeting NIMA (never in mitosis gene A)-related kinase 2 (28). Our previous study reported the tumor suppressive role of miR-128 in paclitaxel-resistant NSCLC by targeting MUC1-C and BMI-1 in CSCs (19). Furthermore, our previous study has suggested that miR-128 targets the c-met/PI3K/AKT pathway in lung CSCs and reverses gefitinib resistance (29). Therefore, BRM270 serves an important role in the prevention of the CSC phenotype, the inhibition of cancer progression and tumor growth, and the suppression of malignant behaviors in chemoresistant NSCLC through the induction of miR-128 overexpression (Fig. 2A) (1). Therefore, BRM270 is an effective compound that may be used to overcome chemoresistance in lung cancer as an alternative or addition to existing conventional drugs.

BRM270 suppresses the proliferation of cervical CSCs by inhibiting SOX2

Cervical cancer (CC) is the fourth most common cause of cancer-associated mortality in females worldwide (30). Surgical resection alone or in combination with adjuvant radiotherapy is commonly used to treat advanced stages of CC. However, this approach only decreases the risk of CC progression and is associated with irreversible morbidity (31). Due to the aggressive nature of CC, multimodality treatments are commonly used, including concurrent chemoradiotherapy or neoadjuvant chemotherapy (NACT) followed by surgery (32,33). However, the application of these approaches, especially NACT, is restricted by the chemoresistance of CC cells to cisplatin, paclitaxel and taxel-based chemotherapies (31). Therefore, increasing the chemotherapeutic efficiency by targeting the underlying mechanisms of chemoresistance is essential for the successful clinical management of CC.

Previous studies have suggested that CC stem cells serve a crucial role in the resistance to conventional therapies (3436). Our recent study reported that BRM270 inhibited CC stem cells by targeting SRY (sex determining region Y)-box 2 (SOX2) (37). SOX2 is a transcription factor that serves a crucial role in the maintenance of CSC stemness and the development of resistance to existing conventional therapies (3841). As BRM270 has the potential to inhibit SOX2 expression, it can block the maintenance of the CSC phenotype from interfering with the emerging chemoresistance (37). BRM270 also negatively affects the progression and metastasis of CC, the EMT and sphere formation of CC stem cells, and tumor initiation (37). It also promotes the apoptosis of CC cells by inhibiting cell proliferation. Furthermore, in CC stem cells, BRM270 downregulates the Wnt/β-Catenin pathway, which is essential to sustain the CSC phenotype (Fig. 2B) (37,42).

Therefore, BRM270 represents an effective alternative to the existing conventional therapies for cervical cancer by targeting CSCs to overcome chemoresistance, thereby improving clinical management.

BRM270 disrupts stem cell properties and synergizes with CCRT to prevent glioblastoma recurrence

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain malignancy in adults (43). Vigorous multimodality treatments, including surgeries, concurrent temozolomide chemo-irradiation and post-radiotherapy adjuvant temozolomide are currently used to treat patients with glioblastoma (44). Despite these treatments, patient prognosis is poor and the 5-year survival rate is less than 10% following the initial diagnosis. Furthermore, the median survival time is ~14.6 months owing to the infiltrative behavior and extreme resistance of cells to radiation and chemotherapy (45). This resistance also leads to the recurrence of glioblastoma following standard cancer therapy. Accumulating evidence suggests that glioblastoma stem cells are the major cause of chemo- and radio-resistance and are largely responsible for tumor recurrence (4649). Therefore, the glioblastoma stem cell population is an important target for the successful clinical management of progressive and recurrent malignant glioblastoma.

A previous study demonstrated that BRM270 targets glioblastoma stem cells, suppressing growth and viability through the induction of apoptosis without affecting normal astrocytes (13). The sub-G0 cell population was significantly increased following the BRM270 treatment, indicating an expanded population of dead cells. Notably, BRM270 treatment did not cause any difference in G1, S or G2/M subpopulations. Furthermore, the stemness properties of glioblastoma stem cells were also suppressed by treatment with BRM270. While BRM270 administration alone targeted the properties of glioblastoma stem cells, combined treatment with concurrent chemoradiotherapy (CCRT) successfully decreased the number of CD15-expressing stem cells and decreased the chance of glioblastoma recurrence (Fig. 2C).

Therefore, BRM270 alone and as a combined treatment with CCRT is effective in suppressing the CSC phenotype, overcoming resistance to radiotherapy and chemotherapy, and preventing the recurrence of malignant glioblastoma.

Pancreatic CSC proliferation is inhibited by BRM270 via the downregulation of sonic hedgehog signaling

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest types of carcinoma, with a median survival time of less than 5–8 months (11). Gemcitabine is used as the first-line drug for PDAC, though intrinsic and acquired resistances remain major challenges. CSCs have been identified in previous studies as crucial players in the resistance of PDAC to existing conventional chemotherapy (11,50).

Our recent study established that BRM270 was capable of inhibiting malignancy and the self-renewal capacity of CD44+ PDAC cells (14). CD44 is a marker of the CSC population and the initiation of cancer, suggesting that BRM270 is able to inhibit CSC populations and stem-like properties of PDAC (51). BRM270 treatment also suppresses PDAC CSC-derived tumor growth via the downregulation of sonic hedgehog signaling in PDAC stem cells (14). The aberrant activation of the sonic hedgehog pathway is one of the major fundamental drivers of PDAC stem cell self-renewal and is associated with decreased survival rates in patients (Fig. 2D) (5254).

Therefore, BRM270 is an effective treatment for PDAC and has the potential to reduce its resistance to existing chemotherapies by inhibiting PDAC stem cells, a crucial player in chemoresistance.

BRM270 inhibits tumorigenesis by suppressing NF-κB signaling in MDR-induced osteosarcoma stem cells

Osteosarcoma is an aggressive malignant tumor that primarily affects the skeletal system, and leads to a 5-year survival rate below 20% (55). It remains a challenge for current therapeutic strategies to effectively treat osteosarcoma due to the MDR of cancer cells to existing chemotherapeutic drugs, including doxorubicin and cisplatin (56,57). The presence of stem cell populations and altered DNA repair mechanisms have been identified as the major underlying methods of MDR in osteosarcoma (57,58). Therefore, targeting these mechanisms would likely inhibit MDR and sensitize osteosarcoma cells to existing drugs.

The capability of BRM270 to circumvent MDR with minimal adverse side effects has been reported (12). BRM270 impacts osteosarcoma MDR by damaging DNA repair mechanisms and negatively affecting CSC populations (12). Our previous study demonstrated that BRM270 disrupts the formation of the microtubule cytoskeleton in doxorubicin-resistant osteosarcoma stem cells, inducing chromosomal condensation and nuclear fragmentation (12). BRM270 also induces programmed cell death and mitotic catastrophe in osteosarcoma stem cells by promoting irreversible DNA damage in the premature apoptosis stage and inhibiting cell proliferation selectively, without affecting the functions of normal cells (12). BRM270 treatment also induces the expression of key pro-apoptotic proteins, including structural maintenance of chromosome 2 (SMC2), Caspase-8, Interleukin-6 (IL-6), Cyclin-dependent kinase 6 (CDK6) and p65 (Fig. 2E) (12).

Therefore, BRM270 is a safe and effective natural compound to treat MDR osteosarcoma by promoting unrepairable DNA damage and cytotoxicity in osteosarcoma stem cells.

BRM270 prevents inflammation-induced hepatocarcinogenesis

Hepatitis B virus (HBV), hepatitis C virus (HCV), non-alcoholic fatty liver disease, alcoholism or aflatoxin exposure are common causes of chronic hepatic injury (59). Persistent inflammation, as a result of chronic liver injury, is strongly associated with hepatocarcinogenesis, leading to the development of hepatocellular carcinoma (HCC) after years of inflammation (59). For example, the inability to clear HCV leads to chronic hepatitis C infection, resulting in inflammation-induced lesions in the liver, hepatic fat accumulation, and progressive fibrosis followed by HCC or cirrhosis (6063). Chronic liver inflammation includes phorbal-12-myristate-13-acetate (PMA)-induced inflammation, which promotes hepatocarcinogenesis and HCC progression. This inflammation induces the expression of numerous inflammatory cytokines, including tumor necrosis factor alpha (TNFα), Interleukin 1 (IL-1), IL-23, IL-6, cyclooxygenase-2 (COX-2), and lymphotoxins (LT) α and β (59,64).

Our recent study reported that this enhanced BRM270 prevents PMA-induced inflammation through suppression of signal transducer and activator of transcription 3 (STAT3) signaling (14). As PMA is a COX-2 inducer and a mediator of inflammation, inhibition of PMA-induced inflammation by BRM270 decreases the expression of IL-6 and COX-2, leading to the suppression of hepatocarcinogenesis progression (14). BRM270 also inhibits hepatic tumor growth and HCC cell metastasis and improves the prognosis of patients with HCC via the inhibition of IL-6 and COX-2 expression (Fig. 3) (14).

Therefore, BRM270 is a natural compound treatment that has the potential to prevent hepatocarcinogenesis induced by inflammation through the downregulation of the IL-6/STAT3/COX-2 axis.

Conclusions

BRM270, a compound made of seven herbal plant extracts, is capable of negatively regulating the resistance of cancer cells to existing conventional therapies by inhibiting the CSC phenotype. BRM270 exerts its antitumor effects against chemoresistance via the suppression of CSC populations and the stem-like properties of CSCs. The compound can be used either as a standalone treatment or synergistically with existing drugs. Furthermore, the functionally enhanced product of BRM270 prevents inflammation-induced hepatocarcinogenesis. BRM270 does not cause any adverse side effects and does not affect normal human cells, but selectively targets cancer cells. Future studies should focus on further understanding the effects of BRM270 on CSCs and chemoresistance and investigate the possibility of BRM270 in clinical use.

Acknowledgements

Not applicable.

Funding

The present study was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Korea (grant no. 2020R1I1A2052417), the Korean Research Institute of Bioscience and Biotechnology Research Initiative Program, Korea (grant nos. KGM5162021 and RBM0112011), and the Scientific Research Team Support Plan of Heilongjiang Bayi Agricultural University, China (grant no. TDJH201904).

Availability of data and materials

Not applicable.

Authors' contributions

NC, HK and TK contributed toward the conception of the study, writing the manuscript and performing the literature search. JK, JL and YHP conducted analysis and revised the manuscript. HNS and TK performed analysis and the quality assessment of the study. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Kwon T, Chandimali N, Huynh DL, Zhang JJ, Kim N, Bak Y, Yoon DY, Yu DY, Lee JC, Gera M, et al: BRM270 inhibits cancer stem cell maintenance via microRNA regulation in chemoresistant A549 lung adenocarcinoma cells. Cell Death Dis. 9:2442018. View Article : Google Scholar : PubMed/NCBI

2 

Toge M, Yokoyama S, Kato S, Sakurai H, Senda K, Doki Y, Hayakawa Y, Yoshimura N and Saiki I: Critical contribution of MCL-1 in EMT-associated chemo-resistance in A549 non-small cell lung cancer. Int J Oncol. 46:1844–1848. 2015. View Article : Google Scholar : PubMed/NCBI

3 

Liu X, Han X, Wan X, He C, Wang Y, Mao A, Yu F, Zhou T, Feng L, Zhang P, et al: SPZ1 is critical for chemoresistance and aggressiveness in drug-resistant breast cancer cells. Biochem Pharmacol. 156:43–51. 2018. View Article : Google Scholar : PubMed/NCBI

4 

Hudson AL, Weir C, Moon E, Harvie R, Klebe S, Clarke SJ, Pavlakis N and Howell VM: Establishing a panel of chemo-resistant mesothelioma models for investigating chemo-resistance and identifying new treatments for mesothelioma. Sci Rep. 4:61522014. View Article : Google Scholar : PubMed/NCBI

5 

Roy L and Cowden Dahl KD: Can stemness and chemoresistance be therapeutically targeted via signaling pathways in ovarian cancer? Cancers (Basel). 10:2412018. View Article : Google Scholar

6 

Kim TW, Lee SY, Kim M, Cheon C, Jang BH, Shin YC and Ko SG: DSGOST regulates resistance via activation of autophagy in gastric cancer. Cell Death Dis. 9:6492018. View Article : Google Scholar : PubMed/NCBI

7 

Chen Y, Zhu J and Zhang W: Antitumor effect of traditional Chinese herbal medicines against lung cancer. Anticancer Drugs. 25:983–991. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Ko JK and Auyeung KK: Target-oriented mechanisms of novel herbal therapeutics in the chemotherapy of gastrointestinal cancer and inflammation. Curr Pharm Des. 19:48–66. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Wang Q, Acharya N, Liu Z, Zhou X, Cromie M, Zhu J and Gao W: Enhanced anticancer effects of Scutellaria barbata D. Don in combination with traditional Chinese medicine components on non-small cell lung cancer cells. J Ethnopharmacol. 217:140–151. 2018. View Article : Google Scholar : PubMed/NCBI

10 

Wang H, Wang F, Wu S, Liu Z, Li T, Mao L, Zhang J, Li C, Liu C and Yang Y: Traditional herbal medicine-derived sulforaphene promotes mitophagic cell death in lymphoma cells through CRM1-mediated p62/SQSTM1 accumulation and AMPK activation. Chem Biol Interact. 281:11–23. 2018. View Article : Google Scholar : PubMed/NCBI

11 

Chandimali N, Huynh DL, Jin WY and Kwon T: Combination effects of hispidin and gemcitabine via inhibition of stemness in pancreatic cancer stem cells. Anticancer Res. 38:3967–3975. 2018. View Article : Google Scholar : PubMed/NCBI

12 

Mongre RK, Sodhi SS, Ghosh M, Kim JH, Kim N, Park YH, Kim SJ, Heo YJ, Sharma N and Jeong DK: The novel inhibitor BRM270 downregulates tumorigenesis by suppression of NF-KB signaling cascade in MDR-induced stem like cancer-initiating cells. Int J Oncol. 46:2573–2585. 2015. View Article : Google Scholar : PubMed/NCBI

13 

Jeon HY, Park CG, Ham SW, Choi SH, Lee SY, Kim JY, Seo S, Jin X, Kim JK, Eun K, et al: BRM270, a compound from natural plant extracts, inhibits glioblastoma stem cell properties and glioblastoma recurrence. J Med Food. 20:838–845. 2017. View Article : Google Scholar : PubMed/NCBI

14 

Huynh DL, Koh H, Chandimali N, Zhang JJ, Kim N, Kang TY, Ghosh M, Gera M, Park YH, Kwon T and Jeong DK: BRM270 inhibits the proliferation of CD44 positive pancreatic ductal adenocarcinoma cells via downregulation of sonic hedgehog signaling. Evid Based Complement Alternat Med. 2019:86204692019. View Article : Google Scholar : PubMed/NCBI

15 

Choi BY, Joo JC, Lee YK, Jang IS, Park SJ and Park YJ: Anti-cancer effect of Scutellaria baicalensis in combination with cisplatin in human ovarian cancer cell. BMC Complement Altern Med. 17:2772017. View Article : Google Scholar : PubMed/NCBI

16 

Lu C, Wang H, Chen S, Yang R, Li H and Zhang G: Baicalein inhibits cell growth and increases cisplatin sensitivity of A549 and H460 cells via miR-424-3p and targeting PTEN/PI3K/Akt pathway. J Cell Mol Med. 22:2478–2487. 2018. View Article : Google Scholar : PubMed/NCBI

17 

Wang Y, Wang H, Zhou R, Zhong W, Lu S, Ma Z and Chai Y: Baicalin inhibits human osteosarcoma cells invasion, metastasis, and anoikis resistance by suppressing the transforming growth factor-β1-induced epithelial-to-mesenchymal transition. Anticancer Drugs. 28:581–587. 2017. View Article : Google Scholar : PubMed/NCBI

18 

Zhao R, Gao X, Cai Y, Shao X, Jia G, Huang Y, Qin X, Wang J and Zheng X: Antitumor activity of Portulaca oleracea L. polysaccharides against cervical carcinoma in vitro and in vivo. Carbohydr Polym. 96:376–383. 2013. View Article : Google Scholar : PubMed/NCBI

19 

Koh H, Park H, Chandimali N, Huynh DL, Zhang JJ, Ghosh M, Gera M, Kim N, Bak Y, Yoon DY, et al: MicroRNA-128 suppresses paclitaxel-resistant lung cancer by inhibiting MUC1-C and BMI-1 in cancer stem cells. Oncotarget. 8:110540–110551. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Pazhouhandeh M, Samiee F, Boniadi T, Khedmat AF, Vahedi E, Mirdamadi M, Sigari N, Siadat SD, Vaziri F, Fateh A, et al: Comparative network analysis of patients with non-small cell lung cancer and smokers for representing potential therapeutic targets. Sci Rep. 7:138122017. View Article : Google Scholar : PubMed/NCBI

21 

Lam WK and Watkins DN: Lung cancer: Future directions. Respirology. 12:471–477. 2007. View Article : Google Scholar : PubMed/NCBI

22 

Kwon T, Rho JK, Lee JC, Park YH, Shin HJ, Cho S, Kang YK, Kim BY, Yoon DY and Yu DY: An important role for peroxiredoxin II in survival of A549 lung cancer cells resistant to gefitinib. Exp Mol Med. 47:e1652015. View Article : Google Scholar : PubMed/NCBI

23 

Ham SY, Kwon T, Bak Y, Yu JH, Hong J, Lee SK, Yu DY and Yoon DY: Mucin 1-mediated chemo-resistance in lung cancer cells. Oncogenesis. 5:e1852016. View Article : Google Scholar : PubMed/NCBI

24 

Lin Y and Wu Z: MicroRNA-128 inhibits proliferation and invasion of glioma cells by targeting COX-2. Gene. 658:63–69. 2018. View Article : Google Scholar : PubMed/NCBI

25 

Liang X, Shangguan W, Zhang M, Mei S, Wang L and Yang R: MiR-128 enhances dendritic cell-mediated anti-tumor immunity via targeting of p38. Mol Med Rep. 16:1307–1313. 2017. View Article : Google Scholar : PubMed/NCBI

26 

Liu X, Liang Z, Gao K, Li H, Zhao G, Wang S and Fang J: MicroRNA-128 inhibits EMT of human osteosarcoma cells by directly targeting integrin α2. Tumour Biol. 37:7951–7957. 2016. View Article : Google Scholar : PubMed/NCBI

27 

Hu J, Cheng Y, Li Y, Jin Z, Pan Y, Liu G, Fu S, Zhang Y, Feng K and Feng Y: MicroRNA-128 plays a critical role in human non-small cell lung cancer tumourigenesis, angiogenesis and lymphangiogenesis by directly targeting vascular endothelial growth factor-C. Eur J Cancer. 50:2336–2350. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Zhao D, Han W, Liu X, Cui D and Chen Y: MicroRNA-128 promotes apoptosis in lung cancer by directly targeting NIMA-related kinase 2. Thorac Cancer. 8:304–311. 2017. View Article : Google Scholar : PubMed/NCBI

29 

Jiang J, Feng X, Zhou W, Wu Y and Yang Y: MiR-128 reverses the gefitinib resistance of the lung cancer stem cells by inhibiting the c-met/PI3K/AKT pathway. Oncotarget. 7:73188–73199. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Sikander M, Hafeez BB, Malik S, Alsayari A, Halaweish FT, Yallapu MM, Chauhan SC and Jaggi M: Cucurbitacin D exhibits potent anti-cancer activity in cervical cancer. Sci Rep. 6:365942016. View Article : Google Scholar : PubMed/NCBI

31 

Zhang J, Zhang Y, Liu S, Zhang Q, Wang Y, Tong L, Chen X, Ji Y, Shang Q, Xu B, et al: Metadherin confers chemoresistance of cervical cancer cells by inducing autophagy and activating ERK/NF-κB pathway. Tumour Biol. 34:2433–2440. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Burzawa J, Gonzales N and Frumovitz M: Challenges in the diagnosis and management of cervical neuroendocrine carcinoma. Expert Rev Anticancer Ther. 15:805–810. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Colombo N and Peiretti M: Critical review of neoadjuvant chemotherapy followed by surgery for locally advanced cervical cancer. Int J Gynecol Cancer. 20 (11 Suppl 2):S47–S48. 2010. View Article : Google Scholar : PubMed/NCBI

34 

Chhabra R: Cervical cancer stem cells: Opportunities and challenges. J Cancer Res Clin Oncol. 141:1889–1897. 2015. View Article : Google Scholar : PubMed/NCBI

35 

Huang R and Rofstad EK: Cancer stem cells (CSCs), cervical CSCs and targeted therapies. Oncotarget. 8:35351–35367. 2017. View Article : Google Scholar : PubMed/NCBI

36 

Wang L, Guo H, Lin C, Yang L and Wang X: Enrichment and characterization of cancer stemlike cells from a cervical cancer cell line. Mol Med Rep. 9:2117–2123. 2014. View Article : Google Scholar : PubMed/NCBI

37 

Chandimali N, Sun HN, Park YH and Kwon T: BRM270 suppresses cervical cancer stem cell characteristics and progression by inhibiting SOX2. In Vivo. 34:1085–1094. 2020. View Article : Google Scholar : PubMed/NCBI

38 

Balahmar RM, Boocock DJ, Coveney C, Ray S, Vadakekolathu J, Regad T, Ali S and Sivasubramaniam S: Identification and characterisation of NANOG+/ OCT-4high/SOX2+ doxorubicin-resistant stem-like cells from transformed trophoblastic cell lines. Oncotarget. 9:7054–7065. 2018. View Article : Google Scholar : PubMed/NCBI

39 

Piva M, Domenici G, Iriondo O, Rábano M, Simões BM, Comaills V, Barredo I, López-Ruiz JA, Zabalza I, Kypta R and Vivanco Md: Sox2 promotes tamoxifen resistance in breast cancer cells. EMBO Mol Med. 6:66–79. 2014. View Article : Google Scholar : PubMed/NCBI

40 

Li Y, Chen K, Li L, Li R, Zhang J and Ren W: Overexpression of SOX2 is involved in paclitaxel resistance of ovarian cancer via the PI3K/Akt pathway. Tumour Biol. 36:9823–9828. 2015. View Article : Google Scholar : PubMed/NCBI

41 

Jin Y, Jiang Z, Guan X, Chen Y, Tang Q, Wang G and Wang X: miR-450b-5p suppresses stemness and the development of chemoresistance by targeting SOX2 in colorectal cancer. DNA Cell Biol. 35:249–256. 2016. View Article : Google Scholar : PubMed/NCBI

42 

Manzo-Merino J, Contreras-Paredes A, Vazquez-Ulloa E, Rocha-Zavaleta L, Fuentes-Gonzalez AM and Lizano M: The role of signaling pathways in cervical cancer and molecular therapeutic targets. Arch Med Res. 45:525–539. 2014. View Article : Google Scholar : PubMed/NCBI

43 

Safa AR, Saadatzadeh MR, Cohen-Gadol AA, Pollok KE and Bijangi-Vishehsaraei K: Emerging targets for glioblastoma stem cell therapy. J Biomed Res. 30:19–31. 2016. View Article : Google Scholar : PubMed/NCBI

44 

Zhu JJ and Wong ET: Personalized medicine for glioblastoma: Current challenges and future opportunities. Curr Mol Med. 13:358–367. 2013. View Article : Google Scholar : PubMed/NCBI

45 

Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, et al: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10:459–466. 2009. View Article : Google Scholar : PubMed/NCBI

46 

Garrido W, Rocha JD, Jaramillo C, Fernandez K, Oyarzun C, San Martin R and Quezada C: Chemoresistance in high-grade gliomas: Relevance of adenosine signalling in stem-like cells of glioblastoma multiforme. Curr Drug Targets. 15:931–942. 2014. View Article : Google Scholar : PubMed/NCBI

47 

Bischof J, Westhoff MA, Wagner JE, Halatsch ME, Trentmann S, Knippschild U, Wirtz CR and Burster T: Cancer stem cells: The potential role of autophagy, proteolysis, and cathepsins in glioblastoma stem cells. Tumour Biol. 39:10104283176922272017. View Article : Google Scholar : PubMed/NCBI

48 

Uribe D, Torres A, Rocha JD, Niechi I, Oyarzún C, Sobrevia L, San Martín R and Quezada C: Multidrug resistance in glioblastoma stem-like cells: Role of the hypoxic microenvironment and adenosine signaling. Mol Aspects Med. 55:140–151. 2017. View Article : Google Scholar : PubMed/NCBI

49 

Safari M and Khoshnevisan A: Cancer stem cells and chemoresistance in glioblastoma multiform: A review article. J Stem Cells. 10:271–285. 2015.PubMed/NCBI

50 

Cioffi M, Trabulo SM, Sanchez-Ripoll Y, Miranda-Lorenzo I, Lonardo E, Dorado J, Reis Vieira C, Ramirez JC, Hidalgo M, Aicher A, et al: The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells. Gut. 64:1936–1948. 2015. View Article : Google Scholar : PubMed/NCBI

51 

Ju SY, Chiou SH and Su Y: Maintenance of the stemness in CD44(+) HCT-15 and HCT-116 human colon cancer cells requires miR-203 suppression. Stem Cell Res. 12:86–100. 2014. View Article : Google Scholar : PubMed/NCBI

52 

Rosow DE, Liss AS, Strobel O, Fritz S, Bausch D, Valsangkar NP, Alsina J, Kulemann B, Park JK, Yamaguchi J, et al: Sonic hedgehog in pancreatic cancer: From bench to bedside, then back to the bench. Surgery. 152 (3 Suppl 1):S19–S32. 2012. View Article : Google Scholar : PubMed/NCBI

53 

Song L, Chen X, Wang P, Gao S, Qu C and Liu L: Effects of baicalein on pancreatic cancer stem cells via modulation of sonic hedgehog pathway. Acta Biochim Biophys Sin (Shanghai). 50:586–596. 2018. View Article : Google Scholar : PubMed/NCBI

54 

Li SH, Fu J, Watkins DN, Srivastava RK and Shankar S: Sulforaphane regulates self-renewal of pancreatic cancer stem cells through the modulation of Sonic hedgehog-GLI pathway. Mol Cell Biochem. 373:217–227. 2013. View Article : Google Scholar : PubMed/NCBI

55 

Zhou W, Hao M, Du X, Chen K, Wang G and Yang J: Advances in targeted therapy for osteosarcoma. Discov Med. 17:301–307. 2014.PubMed/NCBI

56 

Kun-Peng Z, Xiao-Long M and Chun-Lin Z: Overexpressed circPVT1, a potential new circular RNA biomarker, contributes to doxorubicin and cisplatin resistance of osteosarcoma cells by regulating ABCB1. Int J Biol Sci. 14:321–330. 2018. View Article : Google Scholar : PubMed/NCBI

57 

Wang ZD, Wang RZ, Xia YZ, Kong LY and Yang L: Reversal of multidrug resistance by icaritin in doxorubicin-resistant human osteosarcoma cells. Chin J Nat Med. 16:20–28. 2018.PubMed/NCBI

58 

Qi XT, Li YL, Zhang YQ, Xu T, Lu B, Fang L, Gao JQ, Yu LS, Zhu DF, Yang B, et al: KLF4 functions as an oncogene in promoting cancer stem cell-like characteristics in osteosarcoma cells. Acta Pharmacol Sin. 40:546–555. 2019. View Article : Google Scholar : PubMed/NCBI

59 

Vescovo T, Refolo G, Vitagliano G, Fimia GM and Piacentini M: Molecular mechanisms of hepatitis C virus-induced hepatocellular carcinoma. Clin Microbiol Infect. 22:853–861. 2016. View Article : Google Scholar : PubMed/NCBI

60 

Wu Q, Chen JX, Chen Y, Cai LL, Wang XZ, Guo WH and Zheng JF: The chemokine receptor CCR10 promotes inflammation-driven hepatocarcinogenesis via PI3K/Akt pathway activation. Cell Death Dis. 9:2322018. View Article : Google Scholar : PubMed/NCBI

61 

Yan HX, Wu HP, Zhang HL, Ashton C, Tong C, Wu H, Qian QJ, Wang HY and Ying QL: p53 promotes inflammation-associated hepatocarcinogenesis by inducing HMGB1 release. J Hepatol. 59:762–768. 2013. View Article : Google Scholar : PubMed/NCBI

62 

Huan HB, Wen XD, Chen XJ, Wu L, Wu LL, Zhang L, Yang DP, Zhang X, Bie P, Qian C and Xia F: Sympathetic nervous system promotes hepatocarcinogenesis by modulating inflammation through activation of alpha1-adrenergic receptors of Kupffer cells. Brain Behav Immun. 59:118–134. 2017. View Article : Google Scholar : PubMed/NCBI

63 

Li C, Deng M, Hu J, Li X, Chen L, Ju Y, Hao J and Meng S: Chronic inflammation contributes to the development of hepatocellular carcinoma by decreasing miR-122 levels. Oncotarget. 7:17021–17034. 2016. View Article : Google Scholar : PubMed/NCBI

64 

Jung IH, Choi JH, Chung YY, Lim GL, Park YN and Park SW: Predominant activation of JAK/STAT3 pathway by interleukin-6 is implicated in hepatocarcinogenesis. Neoplasia. 17:586–597. 2015. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October-2020
Volume 20 Issue 4

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Chandimali N, Koh H, Kim J, Lee J, Park YH, Sun H and Kwon T: BRM270 targets cancer stem cells and augments chemo‑sensitivity in cancer (Review). Oncol Lett 20: 103, 2020
APA
Chandimali, N., Koh, H., Kim, J., Lee, J., Park, Y.H., Sun, H., & Kwon, T. (2020). BRM270 targets cancer stem cells and augments chemo‑sensitivity in cancer (Review). Oncology Letters, 20, 103. https://doi.org/10.3892/ol.2020.11964
MLA
Chandimali, N., Koh, H., Kim, J., Lee, J., Park, Y. H., Sun, H., Kwon, T."BRM270 targets cancer stem cells and augments chemo‑sensitivity in cancer (Review)". Oncology Letters 20.4 (2020): 103.
Chicago
Chandimali, N., Koh, H., Kim, J., Lee, J., Park, Y. H., Sun, H., Kwon, T."BRM270 targets cancer stem cells and augments chemo‑sensitivity in cancer (Review)". Oncology Letters 20, no. 4 (2020): 103. https://doi.org/10.3892/ol.2020.11964