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: 2.47). 09/2005; 45(8):872-7. DOI: 10.1177/0091270005276905
Source: PubMed

ABSTRACT 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 · 4.65 Impact Factor
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    • "Dissection of the genetic networks and molecular and cellular interactions of the cancer models generated a rich knowledge about new targets and created new platforms for therapies [5]. However, the resistant nature of cancer cells against traditional anticancer drugs [6], the activity of cancer stem cells [7] and insufficient bioavailability of the anticancer drugs to exert pharmacological effects [8] have become potent challenges during cancer therapies. Although the current cancer therapies offer a notable fight against cancer, they could eventually trigger numerous deleterious side effects. "
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    ABSTRACT: This study demonstrates the effective synthesis of five different sized/shaped Pt NPs, within a narrow size regime of 1-21 nm using a modified methodology and the toxicity/biocompatibility of Pt NPs on Neuro 2A cancer cells was investigated elaborately by using light microscopic observations, tryphan blue exclusion assay, MTT assay and ICP-MS. The Pt NPs-C with sizes 5-6 nm showed superior non-cytotoxic property compared to the other four Pt NPs. These non-cytotoxic Pt NPs were employed for successful photothermal treatment of Neuro 2A cell lines using near-IR 1064 nm of laser irradiation. The Pt NPs-C could generate a 9 °C increase in temperature leading to effective photothermal killing of cancer cells. The MALDI-MS was used to prove the possibility of apoptosis related triggering of cell death in the presence of the Pt NPs. The results confirm that the current approach is an effective platform for in vivo treatment of neuro cancer cells.
    Biomaterials 04/2013; 34(23). DOI:10.1016/j.biomaterials.2013.03.077 · 8.31 Impact Factor
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    • "Fig. 1 demonstrates the relationship between stem cells and cancer cells, which are on opposite ends of the biological scale in the sense that stem cells begin as multipotent cells that become differentiated whereas cancer cells are differentiated cells that lose their defining characteristics. Fig. 1 also demonstrates that the two concepts of cancer stem cells co-exist; there are cancer initiating stem cells that originate as stem cells, but transform into cancer causing cells and secondly, there are cancer derived stem cells which are cancer cells that develop stem-like properties, these cells are better known as MDR cells [30]. In line with the concept that MDR cells can develop stem-like properties and be identified as cancer stem cells, different studies have shown that cell stressors such as hypoxia, which are efficient in inducing cancer aggression and MDR phenotypes, also induce stemlike properties in cancer cells such as the expression of stem cell factor (SCF) [9–17,31]. "
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    ABSTRACT: Inefficiencies in systemic drug delivery and tumor residence as well as micro-environmental selection pressures contribute to the development of multidrug resistance (MDR) in cancer. Characteristics of MDR include abnormal vasculature, regions of hypoxia, up-regulation of ABC-transporters, aerobic glycolysis, and an elevated apoptotic threshold. Nano-sized delivery vehicles are ideal for treating MDR cancer as they can improve the therapeutic index of drugs and they can be engineered to achieve multifunctional parameters. The multifunctional ability of nanocarriers makes them more adept at treating heterogeneous tumor mass than traditional chemotherapy. Nanocarriers also have preferential tumor accumulation via the EPR effect; this accumulation can be further enhanced by actively targeting the biological profile of MDR cells. Perhaps the most significant benefit of using nanocarrier drug delivery to treat MDR cancer is that nanocarrier delivery diverts the effects of ABC-transporter mediated drug efflux; which is the primary mechanism of MDR. This review discusses the capabilities, applications, and examples of multifunctional nanocarriers for the treatment of MDR. This review emphasizes multifunctional nanocarriers that enhance drug delivery efficiency, the application of RNAi, modulation of the tumor apoptotic threshold, and physical approaches to overcome MDR.
    Journal of Controlled Release 04/2011; 155(2):237-47. DOI:10.1016/j.jconrel.2011.03.032 · 7.26 Impact Factor
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