The resistance of breast cancer stem cells to conventional hyperthermia and their sensitivity to nanoparticle-mediated photothermal therapy

Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA.
Biomaterials (Impact Factor: 8.56). 04/2012; 33(10):2961-70. DOI: 10.1016/j.biomaterials.2011.12.052
Source: PubMed

ABSTRACT Breast tumors contain a small population of tumor initiating stem-like cells, termed breast cancer stem cells (BCSCs). These cells, which are refractory to chemotherapy and radiotherapy, are thought to persist following treatment and drive tumor recurrence. We examined whether BCSCs are similarly resistant to hyperthermic therapy, and whether nanoparticles could be used to overcome this resistance. Using a model of triple-negative breast cancer stem cells, we show that BCSCs are markedly resistant to traditional hyperthermia and become enriched in the surviving cell population following treatment. In contrast, BCSCs are sensitive to nanotube-mediated thermal treatment and lose their long-term proliferative capacity after nanotube-mediated thermal therapy. Moreover, use of this therapy in vivo promotes complete tumor regression and long-term survival of mice bearing cancer stem cell-driven breast tumors. Mechanistically, nanotube thermal therapy promotes rapid membrane permeabilization and necrosis of BCSCs. These data suggest that nanotube-mediated thermal treatment can simultaneously eliminate both the differentiated cells that constitute the bulk of a tumor and the BCSCs that drive tumor growth and recurrence.

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Available from: David Carroll, Sep 29, 2015
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    • "The heat sources commonly used are ultrasound, laser-induced heat or radio wave radiation [16]. Hyperthermia in cancer treatment facilitates drug delivery, tumor eradication and it could eventually cause tumor regression if nanotubes are introduced along with thermal therapy [17] [18]. The utilization of heat to treat superficial tumors was described more than 5 millenniums ago in an Egyptian papyrus [19]. "
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    ABSTRACT: The increased number of women diagnosed with breast cancer in industrialized countries is raising the awareness of possible factors influencing this occurrence. The present work is based on a multi-layer transport model to analyze the concentration of toxins present in the breast ducts. The multi-layer model presented describes the transport of caffeine, cimetidine, aspirin and nicotine during the resting mammary gland period. Additionally, the dermal transport of drugs such as nicotine and aspirin into the resting mammary gland is analyzed. In a unique approach we also present the impact of introducing an external heat flux at the boundaries to increase the diffusion of these particles into the breast ducts. Our model predicts the movement of toxins and/or drugs within the resting mammary glands.
    International Journal of Heat and Mass Transfer 06/2015; 85:987-995. DOI:10.1016/j.ijheatmasstransfer.2015.02.040 · 2.38 Impact Factor
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    • "The polymeric spheres can protect the drug from adverse external conditions and control its release [8]. Compared with microspheres, NPs have their own superiority over target effect enhancement and abatement of side effects [9]–[10]. Neovessels in tumor are more permeable for nanoparticles under 400–600 nm to pass, which not only can improve the target function but also can lessen the side effects of anti-tumor drugs[11]. "
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    ABSTRACT: Background 5-Fluorouracil (5-FU) is one of the most classic chemotherapy drugs. Nanoparticle drug delivery vehicles offer superiority over target effect enhancement and abatement of side effects. Little is known however as to the specific effect of nanoparticle on peritoneal dissemination of colon cancer. The aim of this study is to prepare one NPs (nanoparticles) loaded with 5-FU and investigate the characteristic of NPs and the role of it in peritoneal metastasis nodules formation of human colon cancer. Methodology/Principal Findings Prepared the NPs (nanoparticles) loaded with 5-FU (5-Fluorouracil) by PEG-PLGA with the method of double emulsion. Then evaluate the characteristics of the NPs by scanning electron microscopy, analyzing the particle diameter distribution and determining the loading efficiency. Detect the release features of NPs in vitro and in vivo. Nude mice with peritoneal metastases were treated with 5-FU solution or 5-FU-NPs through peritoneal cavity. Count the nodules on peritoneum and mesenterium and survey the size of them. We got NPs with average-diameter of 310 nm. In vitro release test shows NPs can release equably for 5 days with release rate of 99.2%. In vivo, NPs group can keep higher plasma concentration of 5-FU longer than it in solution group. The number of peritoneal dissemination nodule below 1 mm in 5-FU-sol group(17.3±3.5) and 5-FU-NP group(15.2±3.2) is less than control group(27.2±4.7)(P<0.05). The total number of nodules in 5-FU-NP group(28.7±4.2) is significantly smaller than in 5-FU-sol group(37.7±6.3) (P<0.05). Conclusions/Significance The novel anti-tumor nanoparticles loaded with 5-FU by PEG-PLGA can release maintain 5 days and have inhibitory action to peritoneal dissemination of colon cancer in mice.
    PLoS ONE 06/2014; 9(6):e98455. DOI:10.1371/journal.pone.0098455 · 3.23 Impact Factor
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    • "It is well-established that moderate hyperthermia at 39–43°C kills cancer cells and sensitizes cancer cells to chemotherapy or radiotherapy [35]–[38]. Interestingly, human breast CSCs have been reported to be resistant than non-CSCs to hyperthermia applied with water-bath whereas CSCs and non-CSCs were equally vulnerable to nanoparticle-mediated photothermal therapy [39]. A recent study reported that human breast CSCs were resistant to radiotherapy, but hyperthermia with optically activated gold nanoshells markedly increased the sensitivity of CSCs to radiotherapy [40],[41]. "
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    ABSTRACT: Metformin, the most widely prescribed drug for treatment of type 2 diabetes, has been shown to exert significant anticancer effects. Hyperthermia has been known to kill cancer cells and enhance the efficacy of various anti-cancer drugs and radiotherapy. We investigated the combined effects of metformin and hyperthermia against MCF-7 and MDA-MB-231 human breast cancer cell, and MIA PaCa-2 human pancreatic cancer cells. Incubation of breast cancer cells with 0.5-10 mM metformin for 48 h caused significant clonogenic cell death. Culturing breast cancer cells with 30 µM metformin, clinically relevant plasma concentration of metformin, significantly reduced the survival of cancer cells. Importantly, metformin was preferentially cytotoxic to CD44(high)/CD24(low) cells of MCF-7 cells and, CD44(high)/CD24(high) cells of MIA PaCa-2 cells, which are known to be cancer stem cells (CSCs) of MCF-7 cells and MIA PaCa-2 cells, respectively. Heating at 42°C for 1 h was slightly toxic to both cancer cells and CSCs, and it markedly enhanced the efficacy of metformin to kill cancer cells and CSCs. Metformin has been reported to activate AMPK, thereby suppressing mTOR, which plays an important role for protein synthesis, cell cycle progression, and cell survival. For the first time, we show that hyperthermia activates AMPK and inactivates mTOR and its downstream effector S6K. Furthermore, hyperthermia potentiated the effect of metformin to activate AMPK and inactivate mTOR and S6K. Cell proliferation was markedly suppressed by metformin or combination of metformin and hyperthermia, which could be attributed to activation of AMPK leading to inactivation of mTOR. It is conclude that the effects of metformin against cancer cells including CSCs can be markedly enhanced by hyperthermia.
    PLoS ONE 02/2014; 9(2):e87979. DOI:10.1371/journal.pone.0087979 · 3.23 Impact Factor
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