Afatinib Enhances the Efficacy of Conventional Chemotherapeutic Agents by Eradicating Cancer Stem–like Cells

Wang, Xiao Kun; He, Jie; Xu, Jing; Ye, Sheng; Wang, Fang; Zhang, Hui; Huang, Zhen; To, Kenneth K.W.; Li, Fu

doi:10.1158/0008-5472.can-13-3553

Cited by 49 publications

(35 citation statements)

References 45 publications

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“…Drugs, including tyrosine kinase inhibitors, are known to cause lysosomal degradation of ABCG2 and reverse the stemness properties of leukemic stem cells (39,40). In a recent study, Liu et al reported that lncRNA maternally expressed gene 3 is significantly decreased in human lung adenocarcinoma and partially contributes to the cisplatin resistance of lung adenocarcinoma cells (41).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of lncRNA NEAT1 mitigates multidrug resistance by inhibiting ABCG2 in leukemia

et al. 2016

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Abstract. Leukemia is a heterogeneous clonal disorder in which early hematopoietic cells fail to differentiate and do not undergo programmed cell death or apoptosis. Less than one-third of adult patients with leukemia are managed using current therapies due to the emergence of multidrug resistance (MDR), emphasizing the need for newer and more robust approaches. Recent reports have suggested that long non-coding RNAs (lncRNAs) contribute to selective gene expression and, hence, could be manipulated effectively to halt the progression of cancer. However, little is known regarding the role of lncRNA in leukemia. Nuclear paraspeckle assembly transcript 1 (NEAT1) is a nuclear-restricted lncRNA involved in the pathogenesis of certain types of cancer. Deregulated expression of NEAT1 has been reported in a number of human malignancies, including leukemia and other solid tumors. The present study aimed to characterize the role of NEAT1 in the regulation of MDR in leukemia. Using reverse transcription-quantitative polymerase chain reaction, it was demonstrated that NEAT1 messenger RNA (mRNA) expression levels were significantly downregulated in leukemia patient samples compared with those from healthy donors. Furthermore, NEAT1 mRNA expression was repressed in a number of leukemia cell lines, including K562, THP-1, HL-60 and Jurkat cells, compared with peripheral white blood control cells, consistent with the expression observed in patients with leukemia. In addition, the transfection of a NEAT1 overexpression plasmid into K562 and THP-1 leukemia cell lines alleviated MDR induced by cytotoxic agents, such as Alisertib and Bortezomib, through inhibition of ATP-binding cassette G2. Although more robust studies are warranted, the current findings provide the basis for the use of NEAT1 as a novel promising target in the treatment of leukemia.

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Section: Discussionmentioning

confidence: 99%

Overexpression of lncRNA NEAT1 mitigates multidrug resistance by inhibiting ABCG2 in leukemia

et al. 2016

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“…Photofrin II, among the most frequently used photosensitizers, sensitized a CSC-enriched U-87MG human glioblastoma cell to radiation and increased the percentage of apoptotic CSCs [91]. Afatinib, a small-molecule inhibitor of the tyrosine kinases of EGFR, HER2 and HER4, suppressed self-renewal capacity and tumorigenicity and eradicated CSCs by decreasing ABCG2 expression [92]. Caveolin-1 silencing sensitized chemotherapy of breast cancer by limiting the self-renewal ability and promoting the differentiation process of CSCs [93].…”

Section: Implications For New Therapeutic Strategiesmentioning

confidence: 99%

“…Reasonably, preexisting CSCs or quiescent cancer stem-like cells could be killed by inhibitors targeting the molecular abnormality in CSCs. For example, aberrant DNA hypermethylation is critical in regulating the renewal and maintaining the stemness of CSCs, and administration of decitabine (DAC), a DNA hypermethylation inhibitor [98], can overcome drug resistance caused by preexisting CSCs [89, 92]. However, the key point to eradicating iCSCs is to block the dedifferentiation of non-stem cancer cells into iCSCs and to prevent the molecular alterations in signaling pathways involved in the formation of iCSCs [8, 95, 96].…”

Section: Implications For New Therapeutic Strategiesmentioning

confidence: 99%

Induced cancer stem cells generated by radiochemotherapy and their therapeutic implications

Chen

Liao

et al. 2016

Oncotarget

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Local and distant recurrence of malignant tumors following radio- and/or chemotherapy correlates with poor prognosis of patients. Among the reasons for cancer recurrence, preexisting cancer stem cells (CSCs) are considered the most likely cause due to their properties of self-renewal, pluripotency, plasticity and tumorigenicity. It has been demonstrated that preexisting cancer stem cells derive from normal stem cells and differentiated somatic cells that undergo transformation and dedifferentiation respectively under certain conditions. However, recent studies have revealed that cancer stem cells can also be induced from non-stem cancer cells by radiochemotherapy, constituting the subpopulation of induced cancer stem cells (iCSCs). These findings suggest that radiochemotherapy has the side effect of directly transforming non-stem cancer cells into induced cancer stem cells, possibly contributing to tumor recurrence and metastasis. Therefore, drugs targeting cancer stem cells or preventing dedifferentiation of non-stem cancer cells can be combined with radiochemotherapy to improve its antitumor efficacy. The current review is to investigate the mechanisms by which induced cancer stem cells are generated by radiochemotherapy and hence provide new strategies for cancer treatment.

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“…The etiology of cancer is complex and appears to include several mechanisms: i) Normal cells with mutations or epigenetic changes can become cancer cells; ii) normal stem cells can transform into CSCs via specific mechanisms; iii) CSCs can originate from cancer cells that are hierarchically downstream of CSCs but have not differentiated and have acquired the capacity for self-renewal; and iv) cancer cells can be derived from progenitor cells or from more differentiated cells via a dedifferentiation process (EMT) (6,(27)(28)(29)(30)(31)(32). EMT appears to have an important role by endowing cells with some of the characteristics and behaviors of CSCs (33).…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical and clinical trials targeted to eradicate this population have improved prognosis (29,34). Wang et al (32) used afatinib, a small-molecule inhibitor of the epidermal growth factor receptor and erb-b2 receptor tyrosine kinase 2 and 4 tyrosine kinases, in order to prefentially eliminate side population cells with CSC characters in cell lines and patient-derived leukemia cells, by decreasing ATP binding cassette subfamily G member 2 expression. In these cells, afatinib also acted in parallel to suppress self-renewal capacity and tumorigenicity.…”

Section: Discussionmentioning

confidence: 99%

Lithium chloride has a biphasic effect on prostate cancer stem cells and a proportional effect on midkine levels

et al. 2016

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Abstract. Prostate cancer (PCa) is the second most frequent type of cancer in men worldwide and the levels of differentiation growth factor midkine (MK) are increased in PCa. Cancer and/or the treatment process itself may lead to psychiatric disorders. Lithium chloride (LiCl) has anti-manic properties and has been used in cancer therapy; however, it has a queried safety profile. In addition, cancer stem cells are responsible for the heterogeneous phenotype of tumor cells; they are involved in progression, metastasis, recurrence and therapy resistance in various cancer types. The aims of the present study were to investigate the effect of different concentrations of LiCl on PCa stem cells (whether a shift from tumorigenic to non-tumorigenic cells occurs) and to determine if these results can be explained through changes in MK levels. Monolayer and spheroid cultures of human prostate stem cells and non-stem cells were incubated with low (1, 10 µM) and high (100, 500 µM) concentrations of LiCl for 72 h. Cell proliferation, apoptotic indices, MK levels and ultrastructure were evaluated. Cells stimulated with low concentrations showed high proliferation, low apoptotic indices, high MK levels and more healthy ultrastructure. Opposite results were obtained at high concentrations. Furthermore, stem cells were more sensitive to stimulation and more resistant to inhibition than non-stem cells. LiCl exhibited concentration-dependent effects on stem cell and non-stem cell groups. MK levels were not involved in the biphasic effect of LiCl; however, they were proportionally affected. To the best of our knowledge, the present study was the first to show the effect of LiCl on PCa stem cells through MK.

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Afatinib Enhances the Efficacy of Conventional Chemotherapeutic Agents by Eradicating Cancer Stem–like Cells

Cited by 49 publications

References 45 publications

Overexpression of lncRNA NEAT1 mitigates multidrug resistance by inhibiting ABCG2 in leukemia

Overexpression of lncRNA NEAT1 mitigates multidrug resistance by inhibiting ABCG2 in leukemia

Induced cancer stem cells generated by radiochemotherapy and their therapeutic implications

Lithium chloride has a biphasic effect on prostate cancer stem cells and a proportional effect on midkine levels

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