Tumor Cell-selective Synergism of TRAIL- and ATRA-induced Cytotoxicity in Breast Cancer Cells

Reinhardt, Annekathrin; Liu, Hongyu; Ma, Yunsheng; Zhou, Yunyun; Zang, Chuanbing; Habbel, Jan-Piet; Possinger, K.; Eucker, Jan

doi:10.21873/anticanres.12509

Cited by 5 publications

(4 citation statements)

References 47 publications

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“…The IC 50 value of rhTRAIL in each of the cell lines was calculated using a linear regression formula ( y = m x + c) from a scatter plot, whereby the x -axis was the concentration of TRAIL (in log10), y was the percentage of cell viability, m was the gradient, and c was the y -intercept value. The IC 50 value of TRAIL was then calculated by anti-log of the derived TRAIL concentration value (in log10) from 50% of cell viability [138,139].…”

Section: Methodsmentioning

confidence: 99%

Targeting of CD133+ Cancer Stem Cells by Mesenchymal Stem Cell Expressing TRAIL Reveals a Prospective Role of Apoptotic Gene Regulation in Non-Small Cell Lung Cancer

Fakiruddin

Lim

Nordin

et al. 2019

Cancers

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Mesenchymal stem cells (MSCs) are emerging as vehicles for anti-tumor cytotherapy; however, investigation on its efficacy to target a specific cancer stem cell (CSC) population in non-small cell lung cancer (NSCLC) is lacking. Using assays to evaluate cell proliferation, apoptosis, and gene expression, we investigated the efficacy of MSCs expressing tumour necrosis factor (TNF)-related apoptosis inducing ligand (MSC-TRAIL) to target and destroy CD133+ (prominin-1 positive) NSCLC-derived CSCs. Characterization of TRAIL death receptor 5 (DR5) revealed that it was highly expressed in the CD133+ CSCs of both H460 and H2170 cell lines. The human MSC-TRAIL generated in the study maintained its multipotent characteristics, and caused significant tumor cell inhibition in NSCLC-derived CSCs in a co-culture. The MSC-TRAIL induced an increase in annexin V expression, an indicator of apoptosis in H460 and H2170 derived CD133+ CSCs. Through investigation of mitochondria membrane potential, we found that MSC-TRAIL was capable of inducing intrinsic apoptosis to the CSCs. Using pathway-specific gene expression profiling, we uncovered candidate genes such as NFKB1, BAG3, MCL1, GADD45A, and HRK in CD133+ CSCs, which, if targeted, might increase the sensitivity of NSCLC to MSC-TRAIL-mediated inhibition. As such, our findings add credibility to the utilization of MSC-TRAIL for the treatment of NSCLC through targeting of CD133+ CSCs.

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Section: Methodsmentioning

confidence: 99%

Targeting of CD133+ Cancer Stem Cells by Mesenchymal Stem Cell Expressing TRAIL Reveals a Prospective Role of Apoptotic Gene Regulation in Non-Small Cell Lung Cancer

Fakiruddin

Lim

Nordin

et al. 2019

Cancers

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“…β-carotene also enhances the apoptosis of breast cancer cells by enhancing the activation of caspase 3 [ 159 ]. A combination of vitamin A with a chemotherapy drug or pro-apoptotic molecules potentiates breast cancer cell death by decreasing pro-survival Bcl-2, increasing pro-death Bax, and activating caspases [ 160 , 161 , 162 ]. CTCs isolated from breast cancer patients demonstrate an altered apoptotic pathway [ 91 , 92 ], and FSS exposed breast cancer cells decrease the abundance of pro-apoptotic proteins such as caspase 3 [ 29 , 52 ].…”

Section: Antioxidant and Breast Cancer Metastasismentioning

confidence: 99%

Cellular Mechanisms of Circulating Tumor Cells During Breast Cancer Metastasis

Park

Brown

Kim

2020

IJMS

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Circulating tumor cells (CTCs) are cancer cells that detach from the primary site and travel in the blood stream. A higher number of CTCs increases the risk of breast cancer metastasis, and it is inversely associated with the survival rates of patients with breast cancer. Although the numbers of CTCs are generally low and the majority of CTCs die in circulation, the survival of a few CTCs can seed the development of a tumor at a secondary location. An increasing number of studies demonstrate that CTCs undergo modification in response to the dynamic biophysical environment in the blood due in part to fluid shear stress. Fluid shear stress generates reactive oxygen species (ROS), triggers redox-sensitive cell signaling, and alters the function of intracellular organelles. In particular, the mitochondrion is an important target organelle in determining the metastatic phenotype of CTCs. In healthy cells, mitochondria produce adenosine triphosphate (ATP) via oxidative phosphorylation in the electron transport chain, and during oxidative phosphorylation, they produce physiological levels of ROS. Mitochondria also govern death mechanisms such as apoptosis and mitochondrial permeability transition pore opening to, in order eliminate unwanted or damaged cells. However, in cancer cells, mitochondria are dysregulated, causing aberrant energy metabolism, redox homeostasis, and cell death pathways that may favor cancer invasiveness. In this review, we discuss the influence of fluid shear stress on CTCs with an emphasis on breast cancer pathology, then discuss alterations of cellular mechanisms that may increase the metastatic potentials of CTCs.

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“…The dual effects of common chemotherapies in cancer, either as a cytotoxic drug or as a sensitizer to the effect of TRAIL and MSC-TRAIL have also been demonstrated in several tumor xenografts including those of brain cancer [ 40 ], hepatocellular carcinoma [ 41 ], breast cancer [ 42 ] and NSCLC [ 43 ]. Furthermore, TRAIL and MSC-TRAIL either alone or in combination with other chemotherapies have also been shown to be effective in targeting CSCs in breast [ 44 , 45 ] and liver cancer [ 46 ]. Although we have found that MSC-TRAIL was effective in targeting the cell lines and their CSCs, one out of the three NSCLC cell lines used was TRAIL-resistant [ 47 ].…”

Section: Introductionmentioning

confidence: 99%

Chemo-Sensitization of CD133+ Cancer Stem Cell Enhances the Effect of Mesenchymal Stem Cell Expressing TRAIL in Non-Small Cell Lung Cancer Cell Lines

Fakiruddin

Lim

Nordin

et al. 2021

Biology

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Pre-clinical studies have demonstrated the efficacy of mesenchymal stem cells (MSCs) expressing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or MSC-TRAIL against several tumors. However, due to the existence of cancer stem cells (CSCs), some tumors, including non-small cell lung cancer (NSCLC), exhibit TRAIL resistance. This study was designed to evaluate the capacity of using first-line chemotherapies including cisplatin, 5-fluorouracil (5-FU) and vinorelbine to act as a chemo-sensitizer on CD133+ (prominin-1 positive) CSCs derived from NSCLC cell lines (A549, H460 and H2170) for the purpose of MSC-TRAIL-induced inhibition. We showed that MSC-TRAIL was resistant to all three chemotherapies compared to the NSCLC cell lines, suggesting that the chemotherapies had little effect on MSC-TRAIL viability. Pre-treatment using either cisplatin or 5-FU, but not with vinorelbine, was able to increase the efficacy of MSC-TRAIL to kill the TRAIL-resistant A549-derived CSCs. The study also demonstrated that both 5-FU and vinorelbine were an effective chemo-sensitizer, used to increase the anti-tumor effect of MSC-TRAIL against H460- and H2170-derived CSCs. Furthermore, pre-treatment using cisplatin was noted to enhance the effect of MSC-TRAIL in H460-derived CSCs; however, this effect was not detected in the H2170-derived CSCs. These findings suggest that a pre-treatment using certain chemotherapies in NSCLC could enhance the anti-tumor effect of MSC-TRAIL to target the CSCs, and therefore the combination of chemotherapies and MSC-TRAIL may serve as a novel approach for the treatment of NSCLC.

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Tumor Cell-selective Synergism of TRAIL- and ATRA-induced Cytotoxicity in Breast Cancer Cells

Abstract: Abstract. Background

Cited by 5 publications

References 47 publications

Targeting of CD133+ Cancer Stem Cells by Mesenchymal Stem Cell Expressing TRAIL Reveals a Prospective Role of Apoptotic Gene Regulation in Non-Small Cell Lung Cancer

Targeting of CD133+ Cancer Stem Cells by Mesenchymal Stem Cell Expressing TRAIL Reveals a Prospective Role of Apoptotic Gene Regulation in Non-Small Cell Lung Cancer

Cellular Mechanisms of Circulating Tumor Cells During Breast Cancer Metastasis

Chemo-Sensitization of CD133+ Cancer Stem Cell Enhances the Effect of Mesenchymal Stem Cell Expressing TRAIL in Non-Small Cell Lung Cancer Cell Lines

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