Colon Cancer Cells Gene Expression Signature As Response to 5- Fluorouracil, Oxaliplatin, and Folinic Acid Treatment

Negrei, Carolina; Hudiţă, Ariana; Ginghină, Octav; Gălățeanu, Bianca; Voicu, Sorina Nicoleta; Stan, Miriana; Costache, Marieta; Fenga, Concettina; Drakoulis, Nikolaos; Tsatsakis, Aristidis

doi:10.3389/fphar.2016.00172

Cited by 36 publications

(29 citation statements)

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“…Among the most extensively studied polyphenols are RES, EGCG and CUR. Many of the effects attributed to these compounds are linked to their antioxidant and anti-inflammatory properties; however, the multiple mechanisms involved include the modulation of molecular events and signaling pathways associated with cell survival, proliferation, differentiation, migration, angiogenesis, hormonal activities, detoxification enzymes and immune responses (Table II) (72)(73)(74)(75).…”

Section: Resultsmentioning

confidence: 99%

Polyphenols in cancer prevention: New insights (Review)

et al. 2020

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A huge volume of literature data suggests that a diet rich in fruits and vegetables, mostly due to the contribution of natural polyphenols, could reduce the incidence of specific cancers. Resveratrol, epigallocatechin gallate and curcumin are among the most extensively studied polyphenols: The majority of the effects attributed to these compounds are linked to their antioxidant and anti-inflammatory properties. The multiple mechanisms involved include the modulation of molecular events and signaling pathways associated with cell survival, proliferation, differentiation, migration, angiogenesis, hormonal activities, detoxification enzymes and immune responses. Notwithstanding their promising role in cancer prevention and treatment, polyphenols often have a poor bioavailability when administered as pure active principles, representing an important limit to their use. However, the bioavailability and thus the efficacy of these compounds can be improved by their administration in combination with other phytochemicals, with anticancer drugs or in polyphenol-loaded nanotechnology-based delivery systems. The possibility of combining conventional drugs with polyphenols offers very valuable advantages, such as the building of more efficient anticancer therapies with less side-effects on the health of patients. The present review focuses on current knowledge regarding the interactions between natural polyphenols and cancer development in order to gain a clearer comprehension of the potential mechanisms through which individual foods and food components may be exploited to reduce cancer risk. Contents 1. Introduction 2. Literature search 3. Classification of polyphenols 4. Prostate cancer 5. Colon cancer 6. Breast cancer 7. Lung cancer 8. Bladder cancer 9. Skin cancer 10. Pancreatic cancer 11. Leukemia 12. Conclusion

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Section: Resultsmentioning

confidence: 99%

Polyphenols in cancer prevention: New insights (Review)

et al. 2020

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“…Based on this, one could hypothesize that 5-FU exposure induces a similar oxidative stress environment in the cell that generates 8-oxo-dGTP thereby stimulating T>G mutations in a C[T>G]T context. In line with this, 5-FU treatment is less cytotoxic when combined with antioxidants (Fu et al 2014) and ROS production is directly correlated with treatment with 5-FU (Focaccetti et al 2015;Negrei et al 2016).…”

Section: Discussionmentioning

confidence: 52%

5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

Christensen

Roest

Besselink

et al. 2019

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5-Fluorouracil (5-FU) is a chemotherapeutic drug component that is commonly used for the treatment of solid cancers. It is proposed that 5-FU possesses anticancer properties via the interference with nucleotide synthesis and incorporation into DNA. As both mechanisms may have a mutational impact on both surviving tumor and healthy cells, we treated intestinal organoids with 5-FU followed by whole genome sequencing analysis and uncovered a highly characteristic mutational pattern that is dominated by T>G substitutions in a CTT context. Analysis of tumor whole genome sequencing data confirmed that this signature can also be identified in vivo in colorectal and breast cancer patients that have undergone treatment with 5-FU. We also found that more 5-FU mutations are induced in TP53 null backgrounds which may be of clinical relevance. Taken together, our results demonstrate that 5-FU is mutagenic and may drive tumor evolution and increase the risk of secondary malignancies. Furthermore, the identified signature shows a strong resemblance to COSMIC signature 17, the hallmark signature of treatment-naive esophageal and gastric tumors, which indicates that distinct endogenous and exogenous triggers can converge onto highly similar mutational signatures. The use of 5-Fluorouracil (5-FU) as an anticancer agent became routine practice soon after its primary synthesis in 1957, and remains essential in many chemotherapeutic regimens today (Longley, Harkin, and Johnston 2003). The fluoropyrimidines, especially 5-FU, capecitabine, tegafur and cytarabine, are currently the third most commonly used anticancer drug in the treatment of solid cancers, including colorectal and breast cancers, and over two million patients are estimated to be treated with fluoropyrimidines each year (Ezzeldin and Diasio 2004). Response rates of 5-FU as a single drug are 10-15%, but increase drastically (>50% response) when given in combination therapies with leucovorin together with oxaliplatin or irinotecan (i.e. FOLFOX and FOLFIRI, respectively) (de Gramont et al. 2000;Boige et al. 2010;Cameron, Gabra, and Leonard 1994).The antifolate property of fluoropyrimidines is thought to be the principal mechanism of action. Fluoropyrimidines are intracellularly converted into the antifolate 5-fluorodeoxyuridine monophosphate (5-FdUMP) that can form a covalent intermediate with the folate-dependent enzyme thymidylate synthase (TYMS) (Sommer and Santi 1974). Consequently, the formation of dTMP from dUMP is inhibited which results in an imbalance of the nucleotide pool that affects DNA synthesis, possibly through incorporation of uracil, and impairs genome replication, with negative consequences for rapidly dividing cells such as cancer cells. Moreover, it has been proposed that 5-fluorodeoxyuridine triphosphate (5-FdUTP) can be directly incorporated into genomic DNA as well (Pettersen et al. 2011;Huehls et al. 2016). Considering these properties, it is conceivable that fluoropyrimidines have mutagenic potential, although the mutational consequences of 5-FU tr...

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“…The intracellular ROS was estimated using DCFH-DA method [15,16]. The treated bacterial cell suspensions were centrifuged at 4 °C for 30 min at 300 g and the supernatant was treated with 100 μM DCFH-DA for 1 h. The fluorescence intensity was recorded using Shimadzu RF5301PC spectrofluorophotometer (Japan) with an excitation and emission wavelength at 485 nm and 530 nm.…”

Section: Methodsmentioning

confidence: 99%