The effects of proliferation status and cell cycle phase on the responses of single cells to chemotherapy

Granada, Adrián E.; Jiménez, Ana María Jiménez; Stewart-Ornstein, Jacob; Blüthgen, Nils; Reber, Simone; Jambhekar, Ashwini; Lahav, Galit

doi:10.1091/mbc.e19-09-0515

Cited by 35 publications

(33 citation statements)

References 61 publications

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“…Regarding morphology, proliferation, and migration potential, our results from cell lysates are following the studies where cells went into autophagy or senescence [ 3 , 44 ] but we also found the same inhibitory effect of cell lysates on fibroblasts. This is in contradiction to these reports [ 57 , 58 ]. Perhaps this difference of effect can be attributed to different fibroblast cell lines or the concentrations of cell lysates used in these studies.…”

Section: Discussioncontrasting

confidence: 98%

“…For WJ-FBSCM, we also found an inhibitory effect at 24HR from some samples. This initial decrease can be explained by the presence of heterogeneous cells at different phases of the cell cycle and the cell's response to arrest or die or proliferate in response to the treatment [ 57 ]. Both concentrations of BM-FBSCM and WJ-FBSCM (100% and 50%) showed significant inhibition in comparison to FBS control at 96HR and 120HR.…”

Section: Discussionmentioning

confidence: 99%

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An In Vitro Comparison of Anti-Tumoral Potential of Wharton’s Jelly and Bone Marrow Mesenchymal Stem Cells Exhibited by Cell Cycle Arrest in Glioma Cells (U87MG)

Aslam

Abusharieh

Abuarqoub

et al. 2021

Pathol. Oncol. Res.

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The therapeutic potential of mesenchymal stem cells (MSCs) for various malignancies is currently under investigation due to their unique properties. However, many discrepancies regarding their anti-tumoral or pro-tumoral properties have raised uncertainty about their application for anti-cancer therapies. To investigate, if the anti-tumoral or pro-tumoral properties are subjective to the type of MSCs under different experimental conditions we set out these experiments. Three treatments namely cell lysates (CL), serum-free conditioned media and FBS conditioned media (FBSCM) from each of Wharton’s Jelly MSCs and Bone Marrow-MSCs were applied to evaluate the anti-tumoral or pro-tumoral effect on the glioma cells (U87MG). The functional analysis included; Morphological evaluation, proliferation and migration potential, cell cycle analysis, and apoptosis for glioma cells. The fibroblast cell line was added to investigate the stimulatory or inhibitory effect of treatments on the proliferation of the normal cell. We found that cell lysates induced a generalized inhibitory effect on the proliferation of the glioma cells and the fibroblasts from both types of MSCs. Similarly, both types of conditioned media from two types of MSCs exerted the same inhibitory effect on the proliferation of the glioma cells. However, the effect of two types of conditioned media on the proliferation of fibroblasts was stimulatory from BM-MSCs and variable from WJ-MSCs. Moreover, all three treatments exerted a likewise inhibitory effect on the migration potential of the glioma cells. Furthermore, we found that the cell cycle was arrested significantly at the G1 phase after treating cells with conditioned media which may have led to inhibit the proliferative and migratory abilities of the glioma cells (U87MG). We conclude that cell extracts of MSCs in the form of secretome can induce specific anti-tumoral properties in serum-free conditions for the glioma cells particularly the WJ-MSCs and the effect is mediated by the cell cycle arrest at the G1 phase.

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Section: Discussioncontrasting

confidence: 98%

Section: Discussionmentioning

confidence: 99%

An In Vitro Comparison of Anti-Tumoral Potential of Wharton’s Jelly and Bone Marrow Mesenchymal Stem Cells Exhibited by Cell Cycle Arrest in Glioma Cells (U87MG)

Aslam

Abusharieh

Abuarqoub

et al. 2021

Pathol. Oncol. Res.

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“…Without such capability, studies of these events will always be limited to taking a "snapshot" of what is in fact a highly dynamic process, as clearly illustrated in the abovementioned in vitro studies by Rohnalter et al [92], who demonstrated the markedly time-dependent fate of individual cancer cells in cisplatin-treated cultures. Another level of complexity that will ultimately need to be addressed relates to ongoing research into the cellular dynamics of individual DDR components in single cells treated with DNA-damaging agents and how these multiple signals are integrated and translated into cell-fate decisions such as survival, death/apoptosis and dormancy/cytostasis [45,[139][140][141].…”

Section: Discussionmentioning

confidence: 99%

Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy

Murray

Mirzayans

2020

IJMS

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Chemotherapy is intended to induce cancer cell death through apoptosis and other avenues. Unfortunately, as discussed in this article, moderate doses of genotoxic drugs such as cisplatin typical of those achieved in the clinic often invoke a cytostatic/dormancy rather than cytotoxic/apoptosis response in solid tumour-derived cell lines. This is commonly manifested by an extended apoptotic threshold, with extensive apoptosis only being seen after very high/supralethal doses of such agents. The dormancy response can be associated with senescence-like features, polyploidy and/or multinucleation, depending in part on the p53 status of the cells. In most solid tumour-derived cells, dormancy represents a long-term survival mechanism, ultimately contributing to disease recurrence. This review highlights the nonlinearity of key aspects of the molecular and cellular responses to bulky DNA lesions in human cells treated with chemotherapeutic drugs (e.g., cisplatin) or ultraviolet light-C (a widely used tool for unraveling details of the DNA damage-response) as a function of the level of genotoxic stress. Such data highlight the growing realization that targeting dormant cancer cells, which frequently emerge following conventional anticancer treatments, may represent a novel strategy to prevent or, at least, significantly suppress cancer recurrence.

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“…Furthermore, in TMZ-exposed glioma cells, the pre-treatment with LAV-BPIFB4, by reducing senescence ( Figure 3 C–F) and probably by restoring the ability of these cells to reenter the cell cycle (as preliminarily documented in Hek-293 transfected with LAV-BPIFB4 isoforms, unpublished data ) may cause the TMZ-induced toxicity, as suggested by the higher apoptotic rate induced by LAV-BPIFB4 co-treatment ( Figure 3 G,H). In this context, Granada A. et al recently reported the unexpected effect of proliferation status in regulating responses to cisplatin and suggest that slowly proliferating cells within tumors, like those reentering the cell cycle, may be acutely vulnerable to chemotherapy [ 52 ]. In the same way, the response to neoadjuvant chemotherapy has been strongly associated with proliferation of ER + /HER2 − breast cancers [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

The Longevity-Associated Variant of BPIFB4 Reduces Senescence in Glioma Cells and in Patients’ Lymphocytes Favoring Chemotherapy Efficacy

Puca

Lopardo

Montella

et al. 2022

Cells

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Glioblastoma (GBM) is the most common primary brain cancer with the median age at diagnosis around 64 years, thus pointing to aging as an important risk factor. Indeed, aging, by increasing the senescence burden, is configured as a negative prognostic factor for GBM stage. Furthermore, several anti-GBM therapies exist, such as temozolomide (TMZ) and etoposide (ETP), that unfortunately trigger senescence and the secretion of proinflammatory senescence-associated secretory phenotype (SASP) factors that are responsible for the improper burst of (i) tumorigenesis, (ii) cancer metastasis, (iii) immunosuppression, and (iv) tissue dysfunction. Thus, adjuvant therapies that limit senescence are urgently needed. The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) gene previously demonstrated a modulatory activity in restoring age-related immune dysfunction and in balancing the low-grade inflammatory status of elderly people. Based on the above findings, we tested LAV-BPIFB4 senotherapeutic effects on senescent glioblastoma U87-MG cells and on T cells from GBM patients. We interrogated SA-β-gal and HLA-E senescence markers, SASP factors, and proliferation and apoptosis assays. The results highlighted a LAV-BPIFB4 remodeling of the senescent phenotype of GBM cells, enhancement of their sensitivity to temozolomide and a selective reduction of the T cells’ senescence from GBM patients. Overall, these findings candidate LAV-BPIFB4 as an adjuvant therapy for GBM.

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The effects of proliferation status and cell cycle phase on the responses of single cells to chemotherapy

Cited by 35 publications

References 61 publications

An In Vitro Comparison of Anti-Tumoral Potential of Wharton’s Jelly and Bone Marrow Mesenchymal Stem Cells Exhibited by Cell Cycle Arrest in Glioma Cells (U87MG)

An In Vitro Comparison of Anti-Tumoral Potential of Wharton’s Jelly and Bone Marrow Mesenchymal Stem Cells Exhibited by Cell Cycle Arrest in Glioma Cells (U87MG)

Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy

The Longevity-Associated Variant of BPIFB4 Reduces Senescence in Glioma Cells and in Patients’ Lymphocytes Favoring Chemotherapy Efficacy

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