Kangdi Li

Autophagy is considered a cytoprotective function in cancer therapy under certain conditions and is a drug resistance mechanism that represents a clinical obstacle to successful cancer treatment and leads to poor prognosis in cancer patients. Because certain clinical drugs and agents in development have cytoprotective autophagy effects, targeting autophagic pathways has emerged as a potential smarter strategy for cancer therapy. Multiple preclinical and clinical studies have demonstrated that autophagy inhibition augments the efficacy of anticancer agents in various cancers. Autophagy inhibitors, such as chloroquine and hydroxychloroquine, have already been clinically approved, promoting drug combination treatment by targeting autophagic pathways as a means of discovering and developing more novel and more effective cancer therapeutic approaches. We summarize current studies that focus on the antitumor efficiency of agents that induce cytoprotective autophagy combined with autophagy inhibitors. Furthermore, we discuss the challenge and development of targeting cytoprotective autophagy as a cancer therapeutic approach in clinical application. Thus, we need to facilitate the exploitation of appropriate autophagy inhibitors and coadministration delivery system to cooperate with anticancer drugs. This review aims to note optimal combination strategies by modulating autophagy for therapeutic advantage to overcome drug resistance and enhance the effect of antitumor therapies on cancer patients.

Cancer-associated fibroblasts (CAFs) play a critical role in the coevolution of breast tumor cells and their microenvironment by modifying cellular compartments and regulating cancer cell functions via stromal-epithelial dialogue. However, the relationship and interaction between stromal and epithelial cells is still poorly understood. Herein, we revealed that breast cancer cells have a stronger ability to activate fibroblasts and transform them into myofibroblasts (CAF-like) than normal breast epithelial cells, and this stronger ability occurs through paracrine signaling. In turn, myofibroblasts promote the proliferation, epithelial-to-mesenchymal transition (EMT), and stemness of breast cancer cells. Detailed regulatory mechanisms showed that, compared with normal cells, Survivin is overexpressed in breast cancer cells and secreted extracellularly in the form of exosomes, which are then internalized by fibroblasts. Breast cancer cell–derived survivin up-regulates SOD1 expression in fibroblasts and then converts them into myofibroblasts, conversely inducing breast cancer progression in vitro and in vivo. Thus, our results indicate that survivin acts as an activator of the tumor microenvironment and that SOD1 up-regulation in fibroblasts can promote breast cancer progression. These results suggest that targeting survivin and SOD1 may be a potential therapeutic strategy for breast cancer. Cancer-associated fibroblasts (CAFs) play a critical role in the coevolution of breast tumor cells and their microenvironment by modifying cellular compartments and regulating cancer cell functions via stromal-epithelial dialogue. However, the relationship and interaction between stromal and epithelial cells is still poorly understood. Herein, we revealed that breast cancer cells have a stronger ability to activate fibroblasts and transform them into myofibroblasts (CAF-like) than normal breast epithelial cells, and this stronger ability occurs through paracrine signaling. In turn, myofibroblasts promote the proliferation, epithelial-to-mesenchymal transition (EMT), and stemness of breast cancer cells. Detailed regulatory mechanisms showed that, compared with normal cells, Survivin is overexpressed in breast cancer cells and secreted extracellularly in the form of exosomes, which are then internalized by fibroblasts. Breast cancer cell–derived survivin up-regulates SOD1 expression in fibroblasts and then converts them into myofibroblasts, conversely inducing breast cancer progression in vitro and in vivo. Thus, our results indicate that survivin acts as an activator of the tumor microenvironment and that SOD1 up-regulation in fibroblasts can promote breast cancer progression. These results suggest that targeting survivin and SOD1 may be a potential therapeutic strategy for breast cancer. Breast cancer is a serious threat to the health and lives of women worldwide because its global incidence and mortality rate are 11.6 and 6.6%, respectively, according to 2018 cancer statistics (1Bray F. Ferlay J. Soerjomataram I. Siegel R.L. Torre L.A. Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin. 2018; 68 (30207593): 394-42410.3322/caac.21492Crossref PubMed Scopus (33702) Google Scholar). Although many strategies have been developed for breast cancer treatment, patients still suffer from a low 5-year survival rate, which is caused mainly by recurrence and metastasis. Recently, accumulating evidence has suggested that the tumor microenvironment (TME) plays a crucial role in the initiation, treatment, mobility, and relapse of breast cancer (2Quail D.F. Joyce J.A. Microenvironmental regulation of tumor progression and metastasis.Nat. Med. 2013; 19 (24202395): 1423-143710.1038/nm.3394Crossref PubMed Scopus (3313) Google Scholar). The TME is a complex and dynamically changing group of cells created during tumor progression that is composed mainly of stromal cell components, such as fibroblasts, macrophages, adipocytes, endothelial cells, inflammatory cells, and extracellular matrix (3Hanahan D. Coussens L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment.Cancer Cell. 2012; 21 (22439926): 309-32210.1016/j.ccr.2012.02.022Abstract Full Text Full Text PDF PubMed Scopus (2357) Google Scholar, 4Meads M.B. Gatenby R.A. Dalton W.S. Environment-mediated drug resistance: a major contributor to minimal residual disease.Nat. Rev. Cancer. 2009; 9 (19693095): 665-67410.1038/nrc2714Crossref PubMed Scopus (556) Google Scholar). Previous reports indicate that it is derived from paracrine signaling, mediated mainly by extracellular cytokines and exosomes, which contribute to the communication between various components of the TME and maintain the malignant states of breast cancer cells (5Scheel C. Eaton E.N. Li S.H.-J. Chaffer C.L. Reinhardt F. Kah K.-J. Bell G. Guo W. Rubin J. Richardson A.L. Weinberg R.A. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast.Cell. 2011; 145 (21663795): 926-94010.1016/j.cell.2011.04.029Abstract Full Text Full Text PDF PubMed Scopus (639) Google Scholar, 6Lyssiotis C.A. Kimmelman A.C. Metabolic interactions in the tumor microenvironment.Trends Cell Biol. 2017; 27 (28734735): 863-87510.1016/j.tcb.2017.06.003Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 7Maia J. Caja S. Strano Moraes M.C. Couto N. Costa-Silva B. Exosome-based cell-cell communication in the tumor microenvironment.Front. Cell Dev. Biol. 2018; 6 (29515996): 1810.3389/fcell.2018.00018Crossref PubMed Scopus (251) Google Scholar). Specifically, the paracrine signaling of stromal cells is important in cancer progression because it regulates cancer cell proliferation, epithelial-to-mesenchymal transition (EMT), stemness and chemoresistance, which result in the synergistic effect of cancer cells and their microenvironment (8Mao Y. Keller E.T. Garfield D.H. Shen K. Wang J. Stromal cells in tumor microenvironment and breast cancer.Cancer Metastasis Rev. 2013; 32 (23114846): 303-31510.1007/s10555-012-9415-3Crossref PubMed Scopus (385) Google Scholar). According to the special anatomical structure of the human mammary gland, cancer-associated fibroblasts (CAFs) are the most abundant components in the breast tumor microenvironment and are pivotal to the proliferation, invasion, angiogenesis, and drug resistance of breast cancer cells (9Ali S. Coombes R.C. Endocrine-responsive breast cancer and strategies for combating resistance.Nat. Rev. Cancer. 2002; 2 (12635173): 101-11210.1038/nrc721Crossref PubMed Scopus (680) Google Scholar, 10Chen X. Song E. Turning foes to friends: targeting cancer-associated fibroblasts.Nat. Rev. Drug Discov. 2019; 18 (30470818): 99-11510.1038/s41573-018-0004-1Crossref PubMed Scopus (328) Google Scholar, 11Tkach M. Théry C. Communication by extracellular vesicles: where we are and where we need to go.Cell. 2016; 164 (26967288): 1226-123210.1016/j.cell.2016.01.043Abstract Full Text Full Text PDF PubMed Scopus (1481) Google Scholar). CAFs, prepared directly from invasive human mammary carcinomas, contain substantial numbers of myofibroblasts that acquire stronger capacities for growth, migration, and extracellular matrix modification and can secrete more tumor-promoting cytokines, such as MMP-2, TGF-β, SDF-1, and IL-6 (12Fang T. Lv H. Lv G. Li T. Wang C. Han Q. Yu L. Su B. Guo L. Huang S. Cao D. Tang L. Tang S. Wu M. Yang W. et al.Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer.Nat. Commun. 2018; 9 (29335551): 19110.1038/s41467-017-02583-0Crossref PubMed Scopus (317) Google Scholar). Recent studies have revealed that some gene mutations in fibroblasts regulate their transformation into CAFs in the breast tumor microenvironment. For example, p62 in fibroblasts promotes tumorigenesis by regulating its own metabolism (13Valencia T. Kim J.Y. Abu-Baker S. Moscat-Pardos J. Ahn C.S. Reina-Campos M. Duran A. Castilla E.A. Metallo C.M. Diaz-Meco M.T. Moscat J. Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis.Cancer Cell. 2014; 26 (25002027): 121-13510.1016/j.ccr.2014.05.004Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). TIMP gene family deficiencies are sufficient for fibroblast activation (14Shimoda M. Principe S. Jackson H.W. Luga V. Fang H. Molyneux S.D. Shao Y.W. Aiken A. Waterhouse P.D. Karamboulas C. Hess F.M. Ohtsuka T. Okada Y. Ailles L. Ludwig A. et al.Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state.Nat. Cell Biol. 2014; 16 (25150980): 889-90110.1038/ncb3021Crossref PubMed Scopus (128) Google Scholar). Recently, we also revealed that the aberrant low expression of p85α in fibroblasts facilitates breast cancer cell metastasis by paracrine WNT10B (15Chen Y. Zeng C. Zhan Y. Wang H. Jiang X. Li W. Aberrant low expression of p85α in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b.Oncogene. 2017; 36 (28394344): 4692-470510.1038/onc.2017.100Crossref PubMed Scopus (62) Google Scholar). Genetic mutations or abnormal expression of specific genes are still considered to be the fundamental causes that alter multiple cellular regulatory pathways and drive breast cancer initiation and progression, although the underlying molecular model of these cancer boosters remains elusive; up to 25% of breast cancer cases are due to one of the few identified rare but highly penetrant genes. Survivin is a member of the inhibitor of apoptosis (IAP) family, also known as BIRC5, or baculoviral inhibitor of apoptosis repeat-containing 5, which is highly expressed in breast cancer cells. It is widely considered a potential marker of cancer and a target for developing anticancer drugs (16Altieri D.C. Survivin, cancer networks and pathway-directed drug discovery.Nat. Rev. Cancer. 2008; 8 (18075512): 61-7010.1038/nrc2293Crossref PubMed Scopus (831) Google Scholar, 17Altieri D.C. Validating survivin as a cancer therapeutic target.Nat. Rev. Cancer. 2003; 3 (12509766): 46-5410.1038/nrc968Crossref PubMed Scopus (1074) Google Scholar, 18Li F. Yang J. Ramnath N. Javle M.M. Tan D. Nuclear or cytoplasmic expression of survivin: what is the significance?.Int. J. Cancer. 2005; 114 (15578717): 509-51210.1002/ijc.20768Crossref PubMed Scopus (216) Google Scholar). An increasing number of studies have demonstrated that survivin promotes the progression of cancer by participating in cell division, angiogenesis, and drug resistance (19Altieri D.C. New wirings in the survivin networks.Oncogene. 2008; 27 (18931693): 6276-628410.1038/onc.2008.303Crossref PubMed Scopus (155) Google Scholar, 20Lladser A. Sanhueza C. Kiessling R. Quest A.F. Is survivin the potential Achilles' heel of cancer?.Adv. Cancer 2011; PubMed Scopus Google Scholar, M. C. D. C. D. N. M.C. L. Quest A.F. Survivin expression promotes tumor via Cancer. 2014; PubMed Scopus Google Scholar). However, the and of extracellular survivin in the breast tumor microenvironment poorly understood. In this we that the exosome-mediated paracrine signaling of survivin in breast cancer cells promotes fibroblast activation into myofibroblasts by and this promotes the proliferation, and stemness of breast cancer. Specifically, compared with normal breast epithelial cells, breast cancer cells more which can be extracellularly through The activation of fibroblasts is mediated by SOD1 up-regulation the of breast exosomal fibroblasts promote the proliferation, migration, and stemness of breast cancer cells in vitro and in vivo. The results of this the role of breast survivin in fibroblasts and survivin and SOD1 targeting as a strategy for the of breast cancer. and expression is the most of myofibroblasts G. G. of and Cell PubMed Scopus Google Scholar). an of from the and we that and expression in breast tumor compared with normal breast Specifically, and expression in breast tumor fibroblasts than in normal fibroblasts, which that a number of fibroblasts are into myofibroblasts in breast cancer breast cancer cells fibroblasts during this we human normal fibroblast cells with from the normal breast cell and the breast cancer cell and with that from normal breast cells, from malignant breast cancer cells the and and which that breast cancer cells have the potential to promote fibroblast into of myofibroblasts of proliferation, and our that from the breast cancer cell and an ability to induce fibroblast we that from and cells and and as as cell and In the results showed that cells and secreted of cytokines with from or cells than with from cells which that fibroblasts are by with of breast cancer. the results in the cell we breast fibroblasts from breast cancer one and one and a of in vitro breast fibroblasts from the and patients more of myofibroblasts than from the and patients and and these indicate that breast cancer cells promote stromal fibroblast activation and transformation into the most critical of myofibroblasts is cancer to the role of fibroblasts in breast cancer progression, we and cells with from breast cells in 2 and cells by cancer cells the and of and cells compared with by normal breast cells. cells by cancer cells stronger of cancer cell than by normal cells 2 and and which epithelial cells to and is known to play an important role in breast cancer progression and drug in and the mesenchymal and and the epithelial marker and cells with breast compared with of that compared with cells, or cells also the stemness of and cells cell also this result we that compared with normal breast cells, breast cancer cells contribute to fibroblast activation and in their own progression. has been as an important of cell communication in the TME S. I. vesicles: and therapeutic Rev. Drug Discov. 2013; PubMed Scopus Google Scholar, A. Kim H. D. in of Cell. 2016; Full Text Full Text PDF PubMed Scopus Google and to the of breast cancer cell–derived are in fibroblast this we the from the of normal breast cells or breast cancer cells and them to cells. that more to the cell in cells than in and cells from by the of and and In the of the marker and the that we cellular results showed that the of secreted in cells than in and cells which is with by cells, we with the and them with cells for The results showed the of in fibroblasts, which that the from various breast epithelial cells into fibroblasts via to the derived from breast cancer cells can fibroblasts to myofibroblasts, we cells with in and the of and in cells by or the and of cells with or compared with 3 and These results that from breast cancer contribute to fibroblast the effect of breast cancer cell–derived in the activation of fibroblasts, the of and by with or of and and to cells. the of in the up-regulation of and expression and the ability of with the of In and to that the ability to promote of fibroblasts compared with the group and and the results that breast fibroblasts into revealed that are a critical of (13Valencia T. Kim J.Y. Abu-Baker S. Moscat-Pardos J. Ahn C.S. Reina-Campos M. Duran A. Castilla E.A. Metallo C.M. Diaz-Meco M.T. Moscat J. Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis.Cancer Cell. 2014; 26 (25002027): 121-13510.1016/j.ccr.2014.05.004Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). Thus, we the of cells with breast cancer cell–derived to the role of in breast fibroblast in from or cells in cells more than from cells. by and expression and ability in cells and and we the expression of genes that in cells with the The and of SOD1 breast and and In breast fibroblasts from and patients expressed more SOD1 and of from that SOD1 expression in CAFs compared with their breast fibroblasts the role of SOD1 in fibroblast we SOD1 in cells and SOD1 the of with SOD1 the activation of cells by breast cancer and and and However, SOD1 and expression and and in cells and and which that SOD1 fibroblasts to the role of SOD1 in cells in regulating the progression of breast cancer cells. The numbers of cells and cells by with from cells compared with with from cells and that the ability of and cells by cells and In cells the and stemness of breast cancer cells and These results suggest that breast cancer cells fibroblasts to myofibroblasts by increasing the SOD1 expression in fibroblasts. we to SOD1 in fibroblasts by from breast cancer cells. the gene expression of breast tumor from we identified genes in breast tumor compared with normal breast and a to the of these genes. these genes by the gene which to be from cancer cells via and in regulation S. Survivin is from cancer cells via 2011; 16 PubMed Scopus Google Scholar, J. Wu S. D. Survivin through signaling during tumor cell apoptosis by PubMed Scopus Google In from that is a between the of survivin and SOD1 in human breast cancer which is composed of tumor epithelial cells and results and also showed that breast cancer cells expressed survivin than normal breast cells and fibroblasts and and of and also contain more survivin than that of cells and breast cancer cell–derived survivin can be into fibroblasts through the of breast survivin in fibroblast we survivin expression with in and cells Survivin the of secreted by or cells in and survivin of and cells the ability to the expression of and in cells. results in and 6 and These results suggest that survivin in breast cancer cells up-regulates SOD1 expression in fibroblasts, fibroblast to the role of and survivin fibroblasts in we and cells into in the mammary of and then fibroblasts from this mammary to of in and and the of and the expression of cells the ability to breast fibroblasts into These results also demonstrated that the expression of SOD1 in mammary fibroblasts is by survivin in the of breast cancer cells. up our that SOD1 in fibroblasts by breast cancer cells, we SOD1 expression in the of breast cancer by and the in and SOD1 more in and than in I. to that SOD1 is important for in which tumor cells or cells with a poorly breast cancer cell cells, and them into cells and cells to form in with the in vitro cells the and of the and and the of cells in breast cancer cells or with cells or cells into through their and their 2 in and SOD1 up-regulation in cells the ability of cells to these results suggest that survivin in breast fibroblasts by promotes cancer and metastasis in The communication between and cancer cells plays a critical role in tumor progression E. the changing of during tumor Cancer Biol. 2005; PubMed Scopus (155) Google but normal fibroblasts are to myofibroblasts remains our the of myofibroblasts in the breast tumor microenvironment. we the of normal breast epithelial cells and breast cancer epithelial cells fibroblast activation and that breast cancer fibroblasts the of myofibroblasts and can promote the proliferation, metastasis and stemness of breast cancer cells. The interaction between breast cancer cells and fibroblasts the of metastasis and drug resistance in breast cancer. are a group of from the of which is widely as crucial for cell A. A. F. The role of and metabolism cancer cells and their Cancer Biol. 2014; PubMed Scopus Google Scholar). In to directly cancer cells, can also breast cancer progression by the metabolism of stromal cells. For a of induces the of in stromal cells and is sufficient to a that promotes tumor F. microenvironment and in breast critical of and 2014; PubMed Scopus Google Scholar). Specifically, in breast promote fibroblast into myofibroblasts through the of and the A. G. S. an between tumor cells and cancer 2016; PubMed Scopus Google Scholar). However, we that a in to fibroblast which the of in cells. the cellular regulation of by and the of the in normal cellular one of the most abundant has been to play a role in human health F. C. and their human Med. 2005; 26 PubMed Scopus Google Scholar). Recent studies also demonstrated that SOD1 the of fibroblasts. For example, SOD1 induces in human fibroblasts G. C.M. M. L. induces in human Biol. 2003; Full Text Full Text PDF PubMed Scopus Google and SOD1 expression and to to and in fibroblasts T. T. J. H. D. M. fibroblast during 2019; PubMed Scopus Google Scholar). with these our that SOD1 converts fibroblasts into Survivin is highly expressed in of breast cancer patients and can be from cancer cells via in regulation S. Survivin is from cancer cells via 2011; 16 PubMed Scopus Google Scholar, J. Wu S. D. Survivin through signaling during tumor cell apoptosis by PubMed Scopus Google Scholar, K. S. G. T. M. N. of survivin and its relationship to of apoptosis in breast Cancer 6 Google Scholar). In demonstrated an exosome-mediated of and in cells A. H. M.C. S. to cancer cells by and of J. Cancer. 2017; PubMed Scopus Google Scholar). However, from these which the regulatory of survivin or in the of cells, we the of exosomal survivin tumor breast cancer cells and stromal fibroblasts. An is one of that communication and is identified as a from to in that is by of cells P.D. and into the Cell Biol. 2013; PubMed Scopus Google Scholar). Recent studies have that are in the growth, drug and metastasis of cancer by and M. Théry C. Communication by extracellular vesicles: where we are and where we need to go.Cell. 2016; 164 (26967288): 1226-123210.1016/j.cell.2016.01.043Abstract Full Text Full Text PDF PubMed Scopus (1481) Google Scholar, C. L. S. and Rev. 2002; 2 PubMed Scopus Google Scholar, H. M. T. R. C. X. I. F. D. M. H. et of the tumor microenvironment and resistance to Cancer Scopus Google Scholar, V. L. E. M. 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R. of fibroblast in the tumor microenvironment.Cancer Biol. PubMed Scopus Google Scholar, D. A. G. E. M. V. H. L.A. et of inflammatory fibroblasts and myofibroblasts in Med. 2017; PubMed Scopus Google we also need to the pathways in the of the survivin in the Discov. 2011; 16 PubMed Scopus Google Scholar, D.C. survivin in cancer.Cancer 2013; PubMed Scopus Google our that targeting survivin and SOD1 is a for cancer In our results that breast exosomal survivin converts fibroblasts into myofibroblasts by In fibroblasts promote the proliferation, and stemness of breast cancer. up-regulation of stromal SOD1 is with a in breast cancer. Thus, the of myofibroblasts has a developing anticancer strategies but also SOD1 as a to cancer the molecular mechanisms of communication between breast cancer cells and stromal fibroblasts and to and strategies for breast cancer. 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L. et for studies of extracellular 2018 a of the for and of the 2018; PubMed Scopus Google Scholar). an number of cells in for 2 and from an of the and in the the and for to the the with to and for For cell treatment, the in For of the in cells, the cells in for and with the cells with an and in the cells and with a For of exosomes, from of in and by The of by cells with a group of cells in cells with and by cells with for cells for for of cells, which in the with and the 6 to and then cells with cells, which in a for cells with The of exosomal survivin in cells by from the Breast and and and the normal breast stromal or fibroblasts from breast cancer patients have or For the a by and the expression between breast cancer and normal breast by the with a of and a rate of The genes with the most expression and by and the by to these genes by and for the that the relationship between survivin and SOD1 in breast cancer by the of the studies by the and of the of and in with the by the of For of fibroblasts from cells, cells, or cells into the mammary of group tumor the and then mammary and fibroblasts from them as Y. L. S. C. N. of normal and cancer-associated fibroblasts from by cell 2013; Google Scholar). For 3 cells or cells with cells and in of These cell or cells into the mammary of group the tumor and by the 32 the and their by For metastasis cells or with 3 cells or cells in of and into the of group a and to cancer cell metastasis. in and are as the S.D. between by considered are the with tumor microenvironment epithelial-to-mesenchymal transition cancer-associated fibroblast interaction

BACKGROUND: Tetrandrine is a bisbenzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephania tetrandra S. Moore. We previously demonstrated that tetrandrine exhibits potent antitumor effects in many types of cancer cells. In this study, we investigated the effects of tetrandrine on human hepatocellular carcinoma (HCC) metastasis. METHODS: The invasion and migration effects were evaluated via wound healing and transwell assays. Immunofluorescence and western blotting analyses were used to investigate the levels of epithelial-mesenchymal transition (EMT)-related protein. A metastasis model was established to investigate the inhibitory effect of tetrandrine on hepatocellular carcinoma metastasis in vivo. RESULTS: Tetrandrine inhibits HCC invasion and migration by preventing cell EMT. The underlying mechanism was closely associated with tetrandrine-induced human liver cell autophagy, which inhibits Wnt/β-catenin pathway activity and decreases metastatic tumor antigen 1 (MTA1) expression to modulate cancer cell metastasis. CONCLUSION: Our findings demonstrate, for the first time, that tetrandrine plays a significant role in the inhibition of human hepatocellular carcinoma metastasis and provide novel insights into the application of tetrandrine in clinical HCC treatment.

Targeting the stemness of triple-negative breast cancer (TNBC) is a potential therapeutic approach for treating TNBC. Tetrandrine, a natural plant alkaloid, has several anticancer effects. Here, we aimed to evaluate the efficacy of tetrandrine in cancer stemness and epithelial to mesenchymal transition (EMT) in TNBC, and to explore the underlying mechanisms. The effects of tetrandrine on cell growth, cell viability, cell stemness capacity, cell migration, and cell invasion, as well as the molecules involved in these processes, were investigated in a cell culture system. An in vivo xenograft tumor and lung metastasis study was performed using nude mice to verify the effects and mechanisms of tetrandrine. Tetrandrine exhibited antiproliferative and cell cycle arrest activities in TNBC cell lines, significantly reduced aldehyde dehydrogenase and CD44[Formula: see text]CD24[Formula: see text] characteristic subpopulation, and successfully prevented mammosphere formation. It suppressed migration and invasion, enhanced anoikis, and regulated the expression of proteins involved in the EMT, including E-cadherin, Vimentin, and Occludin, in both TNBC cells and MDA-MB-231 spheroid cells. Further studies revealed that tetrandrine downregulated the expression of superoxide dismutase 1 (SOD1) and catalase and induced reactive oxygen species (ROS) production, which subsequently contributed to the inhibition of cell EMT and stemness. The in vivo studies also showed that tetrandrine inhibited tumor growth and metastasis of both adherent normal cells, and flow cytometry sorted specific CD44[Formula: see text]CD24[Formula: see text] breast cancer stem cells, which could be rescued by SOD1 overexpression. The results of this study suggest that tetrandrine could effectively inhibit breast cancer stem cell characteristics and the EMT process via the SOD1/ROS signaling pathway. Therefore, tetrandrine can be considered a promising anti-TNBC agent.