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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 2/2018

01-11-2018 | Preclinical study

Fluidic shear stress increases the anti-cancer effects of ROS-generating drugs in circulating tumor cells

Authors: Sagar Regmi, To Sing Fung, Sierin Lim, Kathy Qian Luo

Published in: Breast Cancer Research and Treatment | Issue 2/2018

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Abstract

Purpose

Many anti-cancer drugs are used in chemotherapy; however, little is known about their efficacy against circulating tumor cells (CTCs). In this study, we investigated whether the pulsatile fluidic shear stress (SS) in human arteries can affect the efficacy of anti-cancer drugs.

Methods

Cancer cells were circulated in our microfluidic circulatory system, and their responses to drug and SS treatments were determined using various assays. Breast and cervical cancer cells that stably expressed apoptotic sensor proteins were used to determine apoptosis in real-time by fluorescence resonance energy transfer (FRET)-based imaging microscopy. The occurrence of cell death in non-sensor cells were revealed by annexin V and propidium iodide staining. Cell viability was determined by MTT assay. Intracellular reactive oxygen species (ROS) levels were determined by staining cells with two ROS-detecting dyes: 2′,7′-dichlorofluorescin diacetate and dihydroethidium.

Results

Fluidic SS significantly increased the potency of the ROS-generating drugs doxorubicin (DOX) and cisplatin but had little effect on the non-ROS-generating drugs Taxol and etoposide. Co-treatment with SS and ROS-generating drugs dramatically elevated ROS levels in CTCs, while the addition of antioxidants abolished the pro-apoptotic effects of DOX and cisplatin. More importantly, the synergistic killing effects of SS and DOX or cisplatin were confirmed in circulated lung, breast, and cervical cancer cells, some of which have a strong metastatic ability.

Conclusions

These findings suggest that ROS-generating drugs are more potent than non-ROS-generating drugs for destroying CTCs under pulsatile fluidic conditions present in the bloodstream. This new information is highly valuable for developing novel therapies to eradicate CTCs in the circulation and prevent metastasis.
Literature
1.
Wittekind C, Neid M (2005) Cancer invasion and metastasis. Oncology 69(Suppl. 1):14–16CrossRef
2.
Nicholson C, Vela I, Williams E (2017) Prostate cancer metastasis. Introd Cancer Metastasis 1:33–59CrossRef
3.
Longley D, Johnston P (2005) Molecular mechanisms of drug resistance. J Pathol 205(2):275–292CrossRef
4.
Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2(8):563–572CrossRef
5.
Bernards R, Weinberg RA (2002) Metastasis genes: a progression puzzle. Nature 418(6900):823CrossRef
6.
Alix-Panabières C, Riethdorf S, Pantel K (2008) Circulating tumor cells and bone marrow micrometastasis. Clin Cancer Res 14(16):5013–5021CrossRef
7.
Hughes AD, King MR (2012) Nanobiotechnology for the capture and manipulation of circulating tumor cells. Wiley Interdiscip Rev 4(3):291–309
8.
Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, Tibbe AG, Uhr JW, Terstappen LW (2004) Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 10(20):6897–6904CrossRef
9.
Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse MA, Mitchell E, Miller MC et al (2009) Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol 20(7):1223–1229CrossRef
10.
De Giorgi U, Mego M, Rohren EM, Liu P, Handy BC, Reuben JM, Macapinlac HA, Hortobagyi GN, Cristofanilli M, Ueno NT (2010) 18F-FDG PET/CT findings and circulating tumor cell counts in the monitoring of systemic therapies for bone metastases from breast cancer. J Nucl Med 51(8):1213–1218CrossRef
11.
Maheswaran S, Haber DA (2010) Circulating tumor cells: a window into cancer biology and metastasis. Curr Opin Genet Dev 20(1):96–99CrossRef
12.
Davnall F, Yip CS, Ljungqvist G, Selmi M, Ng F, Sanghera B, Ganeshan B, Miles KA, Cook GJ, Goh V (2012) Assessment of tumor heterogeneity: an emerging imaging tool for clinical practice? Insights Imaging 3(6):573–589CrossRef
13.
Fu A, Ma S, Wei N, Tan BXX, Tan EY, Luo KQ (2016) High expression of MnSOD promotes survival of circulating breast cancer cells and increases their resistance to doxorubicin. Oncotarget 7(31):50239–50257CrossRef
14.
Luo KQ, Yu VC, Pu Y, Chang DC (2001) Application of the fluorescence resonance energy transfer method for studying the dynamics of caspase-3 activation during UV-induced apoptosis in living HeLa cells. Biochem Biophys Res Commun 283(5):1054–1060CrossRef
15.
Anand P, Fu A, Teoh SH, Luo KQ (2015) Application of a fluorescence resonance energy transfer (FRET)-based biosensor for detection of drug-induced apoptosis in a 3D breast tumor model. Biotechnol Bioeng 112(8):1673–1682CrossRef
16.
Regmi S, Fu A, Luo KQ (2017) High shear stresses under exercise condition destroy circulating tumor cells in a microfluidic system. Sci Rep 7:39975CrossRef
17.
Ma S, Fu A, Chiew GGY, Luo KQ (2017) Hemodynamic shear stress stimulates migration and extravasation of tumor cells by elevating cellular oxidative level. Cancer Lett 388:239–248CrossRef
18.
Biganzoli L, Minisini A, Aapro M, Di Leo A (2004) Chemotherapy for metastatic breast cancer. Curr Opin Obstet Gynecol 16(1):37–41CrossRef
19.
Cortés-Funes H, Coronado C (2007) Role of anthracyclines in the era of targeted therapy. Cardiovasc Toxicol 7(2):56–60CrossRef
20.
Dillman RO, Barth NM, VanderMolen LA, Allen K, Beutel LD, Chico S (2005) High-dose chemotherapy and autologous stem cell rescue for metastatic breast cancer: superior survival for tandem compared with single transplants. Am J Clin Oncol 28(3):281–288CrossRef
21.
Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, Altman RB (2011) Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genom 21(7):440CrossRef
22.
Nitiss JL (2002) DNA topoisomerases in cancer chemotherapy: using enzymes to generate selective DNA damage. Curr Opin Investig Drugs 3(10):1512–1516PubMed
23.
Bidwell GL III, Raucher D (2006) Enhancing the antiproliferative effect of topoisomerase II inhibitors using a polypeptide inhibitor of c-Myc. Biochem Pharmacol 71(3):248–256CrossRef
24.
Synowiec E, Hoser G, Bialkowska-Warzecha J, Pawlowska E, Skorski T, Blasiak J (2015) Doxorubicin differentially induces apoptosis, expression of mitochondrial apoptosis-related genes, and mitochondrial potential in BCR-ABL1-expressing cells sensitive and resistant to imatinib. BioMed Res Int 2015(673512):9
25.
Malek AM, Alper SL, Izumo S (1999) Hemodynamic shear stress and its role in atherosclerosis. JAMA 282(21):2035–2042CrossRef
26.
Barnes JM, Nauseef JT, Henry MD (2012) Resistance to fluid shear stress is a conserved biophysical property of malignant cells. PLoS ONE 7(12):e50973CrossRef
27.
Chin LK, Yu JQ, Fu Y, Yu T, Liu AQ, Luo KQ (2011) Production of reactive oxygen species in endothelial cells under different pulsatile shear stresses and glucose concentrations. Lab Chip 11(11):1856–1863CrossRef
28.
Ye MX, Zhao YL, Li Y, Miao Q, Li ZK, Ren XL, Song LQ, Yin H, Zhang J (2012) Curcumin reverses cis-platin resistance and promotes human lung adenocarcinoma A549/DDP cell apoptosis through HIF-1alpha and caspase-3 mechanisms. Phytomedicine 19(8–9):779–787CrossRef
29.
Miao Q, Bi LL, Li X, Miao S, Zhang J, Zhang S, Yang Q, Xie YH, Zhang J, Wang SW (2013) Anticancer effects of bufalin on human hepatocellular carcinoma HepG2 cells: roles of apoptosis and autophagy. Int J Mol Sci 14(1):1370–1382CrossRef
Metadata
Title
Fluidic shear stress increases the anti-cancer effects of ROS-generating drugs in circulating tumor cells
Authors
Sagar Regmi
To Sing Fung
Sierin Lim
Kathy Qian Luo
Publication date
01-11-2018
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 2/2018
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-018-4922-8

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