Long-term resistance to 5-fluorouracil promotes epithelial–mesenchymal transition, apoptosis evasion, autophagy, and reduced proliferation rate in colon cancer cells

Sousa-Squiavinato, Annie Cristhine Moraes; Ramos, Diego Alfonso Arregui; Silveira, Mônica Wanger; Tessmann, Josiane Weber; de-Freitas-Junior, Júlio Cesar Madureira; Morgado‐Díaz, José Andrés

doi:10.1016/j.ejphar.2022.175253

Cited by 9 publications

(9 citation statements)

References 38 publications

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“…To check this, we looked at the mRNA expression levels of two MDR genes namely, ABCB1 and ABCG2 in both dabrafenib- and irinotecan-resistant spheroids using real time RT-PCR analysis. ABCB1, also known as P-glycoprotein, is one of the best characterized ABC transporters involved in restricting the efficacy of treatment in CRC and its elevated levels could predict worse prognosis [ 63 , 64 ]. Moreover, elevated levels of ABCG2 were correlated with chemotherapy resistance in colon cancer cells [ 65 ].…”

Section: Resultsmentioning

confidence: 99%

Investigation of evolutionary dynamics for drug resistance in 3D spheroid model system using cellular barcoding technology

Yalcin,

Yilmaz,

Dilber

et al. 2023

PLoS ONE

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Complex evolutionary dynamics governing the drug resistance is one of the major challenges in cancer treatment. Understanding these mechanisms requires a sequencing technology with higher resolution to delineate whether pre-existing or de novo drug mechanisms are behind the drug resistance. Combining this technology with clinically very relevant model system, namely 3D spheroids, better mimicking tumorigenesis and drug resistance have so far been lacking. Thus, we sought to establish dabrafenib and irinotecan resistant derivatives of barcoded 3D spheroids with the ultimate aim to quantify the selection-induced clonal dynamics and identify the genomic determinants in this model system. We found that dabrafenib and irinotecan induced drug resistance in 3D-HT-29 and 3D-HCT-116 spheroids are mediated by pre-existing and de novo resistant barcodes, indicating the presence of polyclonal drug resistance in this system. Moreover, whole-exome sequencing analysis found chromosomal gains and mutations associated with dabrafenib and irinotecan resistance in 3D-HT-29 and 3D-HCT-116 spheroids. Last, we show that dabrafenib and irinotecan resistance are also mediated by multiple drug resistance by detection of upregulation of the drug efflux pumps, ABCB1 and ABCG2, in our spheroid model system. Overall, we present the quantification of drug resistance and evolutionary dynamics in spheroids for the first time using cellular barcoding technology and the underlying genomic determinants of the drug resistance in our model system.

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Section: Resultsmentioning

confidence: 99%

Investigation of evolutionary dynamics for drug resistance in 3D spheroid model system using cellular barcoding technology

Yalcin,

Yilmaz,

Dilber

et al. 2023

PLoS ONE

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“…When fibroblasts were a part of spheroid TME, HCT116-FUR cells treated by Prop were unable to adhere to the solid surface at all ( Figure 3 D,E). Since increased migration is one of the characteristic features of resistant cells [ 55 , 56 ], its inhibition by a suitable combination of drugs including beta-blockers could fundamentally affect the treatment of resistant CRC tumors. CAIX protein distribution was changed in HCT116-FUR spheroids, we detected CAIX across their entire volume, not only in perinecrotic cells and in areas exceeding the oxygen diffusion capacity ( Figure 2 D and Figure 3 C).…”

Section: Discussionmentioning

confidence: 99%

Propranolol, Promising Chemosensitizer and Candidate for the Combined Therapy through Disruption of Tumor Microenvironment Homeostasis by Decreasing the Level of Carbonic Anhydrase IX

Puzderova,

Belvoncikova,

Grossmannova

et al. 2023

IJMS

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Resistance to chemotherapy represents a persisting medical problem, ranking among main causes of chemotherapy failure and cancer mortality. There is a possibility to utilize and repurpose already existing therapeutics which were not primarily intended for oncological treatment. Overactivation of adrenergic receptors and signaling dysregulation promotes tumor progression, metastatic potential, immune system evasion, tumor angiogenesis and drug resistance. The non-selective beta-blocker propranolol, approved in infantile haemangioma treatment, has a high potential for use in cancer therapy. We analyzed the effects of propranolol and 5-fluorouracil combination on sensitive and resistant cells derived from colorectal carcinoma in monolayers, single-component and co-culture spheroids and in vivo mouse models. Our results revealed that propranolol is able to exert its effect not only in chemosensitive colorectal cells, but also in 5-fluorouracil resistant cells. Propranolol disrupts the hypoxic adaptation machinery by inhibiting HIF1α, carbonic anhydrase IX, and activates apoptosis, which may be important in the management of chemo-resistant patients. We showed that propranolol slows down the growth of xenografts formed from colorectal cancer cells, even from cells already adapted to the β-blocker. We provide clear evidence that blockade of β-adrenergic receptors affects essential signaling pathways modulating tumor microenvironment and thus the response to anticancer therapy. Our findings indicate that propranolol could be repurposed to serve as chemosensitizer in combined therapy aimed at disrupting homeostasis of tumor microenvironment.

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“…This study showed that chronic oxaliplatin resistance in CRC cells leads them to switch to an invasive phenotype and initiates EMT [ 295 ]. Long-term exposure of CRC cells to 5-FU enabled these cells to overcome S-phase arrest, evade apoptosis and activate autophagy which is evident by the up-regulation of LC3B, vimentin, Twist1, Slug, and zeb2 mRNA levels and down-regulation of E-cadherin and Claudin-3 [ 296 ]. These results suggested that CRC cells respond to chemotherapy-induced cell stress by undergoing EMT-plasticity as an adaptive mechanism, leading to cell survival, plasticity, and evasion of apoptosis.…”

Section: Resveratrol Acts As a Chemosensitizer In Crc Cellsmentioning

confidence: 99%

Resveratrol as sensitizer in colorectal cancer plasticity

Brockmueller

Sajeev

Koklesová

et al. 2023

Cancer Metastasis Rev

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Despite tremendous medical treatment successes, colorectal cancer (CRC) remains a leading cause of cancer deaths worldwide. Chemotherapy as monotherapy can lead to significant side effects and chemoresistance that can be linked to several resistance-activating biological processes, including an increase in inflammation, cellular plasticity, multidrug resistance (MDR), inhibition of the sentinel gene p53, and apoptosis. As a consequence, tumor cells can escape the effectiveness of chemotherapeutic agents. This underscores the need for cross-target therapeutic approaches that are not only pharmacologically safe but also modulate multiple potent signaling pathways and sensitize cancer cells to overcome resistance to standard drugs. In recent years, scientists have been searching for natural compounds that can be used as chemosensitizers in addition to conventional medications for the synergistic treatment of CRC. Resveratrol, a natural polyphenolic phytoalexin found in various fruits and vegetables such as peanuts, berries, and red grapes, is one of the most effective natural chemopreventive agents. Abundant in vitro and in vivo studies have shown that resveratrol, in interaction with standard drugs, is an effective chemosensitizer for CRC cells to chemotherapeutic agents and thus prevents drug resistance by modulating multiple pathways, including transcription factors, epithelial-to-mesenchymal transition-plasticity, proliferation, metastasis, angiogenesis, cell cycle, and apoptosis. The ability of resveratrol to modify multiple subcellular pathways that may suppress cancer cell plasticity and reversal of chemoresistance are critical parameters for understanding its anti-cancer effects. In this review, we focus on the chemosensitizing properties of resveratrol in CRC and, thus, its potential importance as an additive to ongoing treatments. Graphical abstract

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Long-term resistance to 5-fluorouracil promotes epithelial–mesenchymal transition, apoptosis evasion, autophagy, and reduced proliferation rate in colon cancer cells

Cited by 9 publications

References 38 publications

Investigation of evolutionary dynamics for drug resistance in 3D spheroid model system using cellular barcoding technology

Investigation of evolutionary dynamics for drug resistance in 3D spheroid model system using cellular barcoding technology

Propranolol, Promising Chemosensitizer and Candidate for the Combined Therapy through Disruption of Tumor Microenvironment Homeostasis by Decreasing the Level of Carbonic Anhydrase IX

Resveratrol as sensitizer in colorectal cancer plasticity

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