Gemcitabine induces cell senescence in human pancreatic cancer cell lines

Song, Yanyu; Baba, Tomohisa; Mukaida, Naofumi

doi:10.1016/j.bbrc.2016.06.063

Cited by 32 publications

(28 citation statements)

References 22 publications

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“…It was previously reported that GEM-resistant pancreatic cancer cells show senescence-associated phenotypes instead of undergoing apoptosis, leading to reversible cellular arrest to evade cell death and the development of GEM resistance. 50 We propose that a similar phenomenon occurs in CC cells treated with GEM.…”

Section: Discussionmentioning

confidence: 60%

FBXW7 modulates malignant potential and cisplatin‐induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1

et al. 2018

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The ubiquitin ligase F‐box and WD repeat domain‐containing 7 (FBXW7) is responsible for degrading diverse oncoproteins and is considered a tumor suppressor in many human cancers. Inhibiting FBXW7 enhances the malignant potential of several cancers. In this study, we aimed to investigate the role of FBXW7 in cholangiocarcinoma. We found that FBXW7 expression was associated with clinicopathological outcomes in cholangiocarcinoma patients. Both disease‐free and overall survival were significantly worse in the low‐FBXW7 group than in the high‐FBXW7 group (P = .001 and P < .001, respectively). Multivariate analysis with the Cox proportional hazards model indicated that FBXW7 was the most important independent prognostic factor for disease‐free (P = .006) and overall (P = .0004) survival. We also showed that the two FBXW7 substrates, NOTCH1 and myeloid cell leukemia sequence 1 (MCL1), regulate cholangiocarcinoma progression. Depletion of FBXW7 resulted in NOTCH1 accumulation and increased cholangiocarcinoma cell migration and self‐renewal. Interestingly, when cells were stimulated with cis‐diamminedichloridoplatinum(II) (cisplatin), FBXW7 suppression induced MCL1 upregulation, which reduced the sensitivity of cholangiocarcinoma cells to apoptosis, indicating that FBXW7‐mediated ubiquitylation is context‐dependent. These results indicate that FBXW7 modulates the malignant potential of cholangiocarcinoma through independent regulation of NOTCH1 and MCL1.

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Section: Discussionmentioning

confidence: 60%

FBXW7 modulates malignant potential and cisplatin‐induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1

et al. 2018

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“…Platinum-based Cisplatin A375, B16F10, B16F10 xenografts SASP, SA-β-gal [64] A2780 SAHF (HP1-γ), morphology, SA-β-gal [68] CNE1 Growth arrest, morphology, SA-β-gal [30] SKOV3, TOV-21G Morphology, SA-β-gal [69] HepG2, SMMC-7721 SA-β-gal, p53, p21 Cip1 , p16 INK4 [70] Follicular lymphoma 3D model SA-β-gal [49] In vivo mouse model (p16-3MR) p16 INK4 [28] Carboplatin H1299, patients' lung tumor samples Cell cycle arrest, SA-β-gal, p16 INK4 , RB, downregulation of cyclin B1 and cyclin D1 [71] Oxaliplatin PROb, CT26 SA-β-gal [72] HepG2, SMMC-7721, patients' colorectal tumor samples SA-β-gal [73] Antimetabolites Methotrexate C85 p53 [74] C85 SA-β-gal [75] MCF-7 SA-β-gal [76] Rat-derived BMSCs and ADSCs SA-β-gal [42] A549 p21 Cip1 , low Ki67, growth arrest, SA-β-gal, increased granularity, morphology, SASP (IL-6, IL-8), γH2AX [43] SH-SY-5Y p21 Cip1 , growth arrest, SA-β-gal, γH2AX [43] HCT116 p21 Cip1 , low Ki67, growth arrest, SA-β-gal, increased granularity, morphology, SASP (IL-8), γH2AX [43] MDA-MB-231 p21 Cip1 , growth arrest, SA-β-gal, morphology, SASP (IL-6, IL-8, VEGF) [43] MCF-7 p21 Cip1 , low Ki67, growth arrest, SA-β-gal, increased granularity, morphology, γH2AX [43] Pemetrexed H1650, A549, H2228, H292, H226 and H1650, A549 xenografts SA-β-gal, morphology, SASP (IL-6, IL-8, IL-1β and MCP-1) [77] A549 SASP, SA-β-gal [78] Gemcitabine Miapaca-2 and Panc-1 SA-β-gal [79] AsPc1, Panc1 SA-β-gal [80] Azacitidine U2OS, MCF7 SA-β-gal, p53, growth arrest [81] TPC-1 SA-β-gal [82] KKU100, HuCCA1, RMCCA1 Morphology, SA-β-gal [83] DU145, LNCaP Morphology, growth arrest, polyploidy [40] Bromodeoxyuridine MNA, STA-NB-10, CLB-Ma mouse xenograft (MYCN-amplified neuroblastoma)…”

Section: Drug Class Drug Name Model/cell Line Senescence Marker Refermentioning

confidence: 99%

“…Gemcitabine, a nucleoside analogue used primarily for the treatment of pancreatic cancer, can generate oxidative stress sufficient to activate senescence in Miapaca-2 and Panc-1 human pancreatic cancer cells marked by growth arrest and SA-β-gal expression [79]. Azacitidine, a pyrimidine analogue used for myelodysplastic syndrome, induces senescence in a variety of cell lines in vitro including U2OS human osteosarcoma, MCF7 breast cancer, TPC-1 papillary thyroid carcinoma, DU145 and LNCaP prostate cancer, and several cholangiocarcinoma cell lines [40,[81][82][83].…”

Section: Antimetabolitesmentioning

confidence: 99%

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Saleh

Bloukh

Carpenter

et al. 2020

Cancers

206

150

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For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse.

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“…101 The active metabolite, dFdCTP, can terminate DNA elongation by incorporating into DNA, finally leading to cell death. 99,102,103 In addition, dFdCDP can inhibit RR by binding to the large subunit (RRM1). 104,105 RRs catalyze the conversion of nucleoside 5′-diphosphates (ie, NDPs) to their corresponding deoxynucleotides (ie, dNDPs), which are phosphorylated to dNTPs for DNA synthesis.…”

Section: Gemcitabine and Its Mechanisms Of Actionmentioning

confidence: 99%

Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

Chen¹,

Zheng²,

Shi³

et al. 2018

IJN

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Despite recent advances in targeted therapies and immunotherapies, chemotherapy using cytotoxic agents remains an indispensable modality in cancer treatment. Recently, there has been a growing emphasis in using nanomedicine in cancer chemotherapy, and several nanomedicines have already been used clinically to treat cancers. There is evidence that formulating small molecular cancer chemotherapeutic agents into nanomedicines significantly modifies their pharmacokinetics and often improves their efficacy. Importantly, cancer cells often develop resistance to chemotherapy, and formulating anticancer drugs into nanomedicines also helps overcome chemoresistance. In this review, we briefly describe the different classes of cancer chemotherapeutic agents, their mechanisms of action and resistance, and evidence of overcoming the resistance using nanomedicines. We then emphasize on gemcitabine and our experience in discovering the unique (stearoyl) gemcitabine solid lipid nanoparticles that are effective against tumor cells resistant to gemcitabine and elucidate the underlying mechanisms. It seems that lysosomes, which are an obstacle in the delivery of many drugs, are actually beneficial for our (stearoyl) gemcitabine solid lipid nanoparticles to overcome tumor cell resistance to gemcitabine.

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Gemcitabine induces cell senescence in human pancreatic cancer cell lines

Cited by 32 publications

References 22 publications

FBXW7 modulates malignant potential and cisplatin‐induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1

FBXW7 modulates malignant potential and cisplatin‐induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

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