Multiple Drug Resistance in Cancer Revisited: The Cancer Stem Cell Hypothesis

Department of Surgery, Division of Thoracic Surgery, University of Pittsburgh Cancer Institute, Pennsilvania, USA.
The Journal of Clinical Pharmacology (Impact Factor: 2.48). 09/2005; 45(8):872-7. DOI: 10.1177/0091270005276905
Source: PubMed


The failure to eradicate cancer may be as fundamental as a misidentification of the target. Current therapies succeed at eliminating bulky disease but often miss a tumor reservoir that is the source of disease recurrence and metastasis. Recent advances in the understanding of tissue development and repair cause us to revisit the process of drug resistance as it applies to oncogenesis and tumor heterogeneity. The cancer stem cell hypothesis states that the cancer-initiating cell is a transformed tissue stem cell, which retains the essential property of self-protection through the activity of multiple drug resistance (MDR) transporters. This resting constitutively drug-resistant cell remains at low frequency among a heterogeneous tumor mass. In the context of this hypothesis, the authors review the discovery of MDR transporters in cancer and normal stem cells and the failure of MDR reversal agents to increase the therapeutic index of substrate antineoplastic agents.

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    • "These findings prompted us to combine sunitinib with a CSCs-targeting drug, in the expectation to improve the outcomes in breast cancer patients. The hypothesis of CSCs has been considered as a milestone in the understanding of drug resistance and cancer recurrence [10] [11]. CSCs in different types of solid tumor possess specific biomarkers to be identified [12] [13] [14]. "
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    ABSTRACT: Growing evidence suggests that the efficacy of sunitinib in breast cancer may be limited by increasing the population of cancer stem-like cells (CSCs). Hence the concurrent use of CSCs-targeting agents is required. Previous results indicated that dopamine receptor (DR) may serve as a potential therapeutic target of anti-CSCs therapies. This study focused on evaluating the effect of dopamine (an agonist of DR) on the enhancement of sunitinib's efficacy in the treatment of drug-resistant breast cancer, investigating the involved activation type of DR pathway and exploring the underlying anti-CSCs mechanisms. MCF-7 cells, MCF-7/Adr cells and breast cancer stem-like cells (BCSCs) were used for in vitro study. Moreover, MCF-7/Adr cells and BCSCs were selected as drug-resistant cell lines and further used for in vivo development of the xenograft animal models. Our results showed that dopamine greatly synergized the inhibitory effect of sunitinib in the drug-resistant cells and strikingly enhanced the response of sunitinib in both xenograft models. It was found that dopamine significantly down-regulated the expression of BCSCs markers (CD44(+)/CD24(-)) in vitro and in vivo. In addition, dopamine remarkably induced the apoptosis of BCSCs, markedly inhibited the Wnt signaling pathway and activated the apoptotic associated signals. The activation of dopamine receptor D1 (D1DR) pathway may be involved in the underlying mechanism as D1DR's antagonist SCH23390 completely reversed the combined effects. In conclusion, dopamine may eradicate CSCs and it significantly enhances the response of sunitinib in the treatment of drug-resistant breast cancer. Copyright © 2015. Published by Elsevier Inc.
    Biochemical pharmacology 03/2015; 95(2). DOI:10.1016/j.bcp.2015.03.013 · 5.01 Impact Factor
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    • "The cancer stem cells (CSCs) are cellswithin a tumor that possess the capacity to self-renew and differentiate into the heterogeneous lineages of cancer cells that comprisethe whole tumor(Singh et al., 2003). Increasing studiesshowed thatdrug-resistant cancercells display a stem-like signature(Donnenberg and Donnenberg, 2005; Vinogradov and Wei, 2012). "
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    ABSTRACT: Themetastasis-associated gene 1 (MTA1) oncogene hasbeen suggested to be involved in the regulation of cancer progression. However, there is still no direct evidence that MTA1 regulates cisplatin (CDDP) resistance, as well as cancer stem cell properties. In this study, we found that MTA1 was enriched in CNE1/CDDP cells. Knock down of MTA1 in CNE1/CDDP cells reversed CSCs properties and CDDP resistance. However, ectopic expression of MTA1 in CNE1 cells induced CSCs phenotypes and CDDP insensitivity. Interestingly, ectopic overexpression of MTA1-induced CSCs properties and CDDP resistance were reversed in CNE1 cells after inhibition of PI3K/Akt by LY294002. In addition, MTA1 expression and Akt activity in CNE1/CDDP cells was much higher than that in CNE1 cells. These results suggested that MTA1 may play a critical role in promoting CDDP resistance in NPC cells by regulatingcancer stem cell properties via thePI3K/Akt signaling pathway. Our findings suggested that MTA1 may be a potential target for overcoming CDDP resistance in NPC therapy.1.
    Molecules and Cells 09/2014; 37(9). DOI:10.14348/molcells.2014.0029 · 2.09 Impact Factor
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    • "Cancer cultures also have a population of stem cells that are responsible for their growth and other characteristics of a tumor's biological properties [55, 57]. The mechanisms responsible for cell resistance against medicines and other substances vary between stem cells and differentiated cells [6, 58, 59, 60]. The analysis of the results of in vitro cytotoxicity tests should be based on separate analysis describing the cytotoxicity for stem cells and separate analysis describing the cytotoxicity for differentiated cells. "
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    ABSTRACT: The α1-adrenoreceptor antagonists, such as terazosin and doxazosin, induce prostate programmed cell death (apoptosis) within prostate epithelial and stromal cells in vitro. This treatment should cause prostate volume decrease, However, this has never been observed in clinical conditions. The aim of this paper is to review the disconnect between these two processes. PubMed and DOAJ were searched for papers related to prostate, apoptosis, and stem cell death. The following key words were used: prostate, benign prostate hyperplasia, programmed cell death, apoptosis, cell death, α1-adrenoreceptor antagonist, α-blockade, prostate epithelium, prostate stroma, stem cells, progenitors, and in vitro models. We have shown how discoveries related to stem cells can influence our understanding of α-blockade treatment for BPH patients. Prostate epithelial and mesenchymal compartments have stem (progenitors) and differentiating cells. These compartments are described in relation to experimental in vitro and in vivo settings. Apoptosis is observed within prostate tissue, but this effect has no clinical significance and cannot lead to prostate shrinkage. In part, this is due to stem cells that are responsible for prostate tissue regeneration and are resistant to apoptosis triggered by α1-receptor antagonists.
    Central European Journal of Urology 08/2013; 66(2):189-194. DOI:10.5173/ceju.2013.02.art19
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