Chemotherapy-associated liver injury in colorectal cancer

Gangi, Alexandra; Lu, Shelly C.

doi:10.1177/1756284820924194

Cited by 32 publications

(29 citation statements)

References 68 publications

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“…Nevertheless, to circumvent possible limitations and/or misleading results unforeseen by us from the LDH assay with normal, non-transformed cells (HUVECs and colon epithelial cells), as such as undetected early induced death (occurring outside the experimental time point evaluated by us) or by eventual LDH degradation in the media of these cells, we decided to assess whether normal colon mucosal organoids would tolerate KAN0438757 treatment. The striking results obtained with intestinal PDOs further supported the idea that KAN0438757 could possibly target tumor cells preserving normal tissues, a very desired scenario in oncological therapeutical approaches, where severe systemic toxicity affects patients’ outcomes [ 52 , 53 , 54 , 55 , 56 ].…”

Section: Discussionmentioning

confidence: 81%

Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo

Oliveira

Goldhardt

Edelmann

et al. 2021

Cancers

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Background: Despite substantial progress made in the last decades in colorectal cancer (CRC) research, new treatment approaches are still needed to improve patients’ long-term survival. To date, the promising strategy to target tumor angiogenesis metabolically together with a sensitization of CRC to chemo- and/or radiotherapy by PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) inhibition has never been tested. Therefore, initial evaluation and validation of newly developed compounds such as KAN0438757 and their effects on CRC cells are crucial steps preceding to in vivo preclinical studies, which in turn may consolidate new therapeutic targets. Materials and Methods: The efficiency of KAN0438757 to block PFKFB3 expression and translation in human CRC cells was evaluated by immunoblotting and real-time PCR. Functional in vitro assays assessed the effects of KAN0438757 on cell viability, proliferation, survival, adhesion, migration and invasion. Additionally, we evaluated the effects of KAN0438757 on matched patient-derived normal and tumor organoids and its systemic toxicity in vivo in C57BL6/N mice. Results: High PFKFB3 expression is correlated with a worse survival in CRC patients. KAN0438757 reduces PFKFB3 protein expression without affecting its transcriptional regulation. Additionally, a concentration-dependent anti-proliferative effect was observed. The migration and invasion capacity of cancer cells were significantly reduced, independent of the anti-proliferative effect. When treating colonic patient-derived organoids with KAN0438757 an impressive effect on tumor organoids growth was apparent, surprisingly sparing normal colonic organoids. No high-grade toxicity was observed in vivo. Conclusion: The PFKFB3 inhibitor KAN0438757 significantly reduced CRC cell migration, invasion and survival. Moreover, on patient-derived cancer organoids KAN0438757 showed significant effects on growth, without being overly toxic in normal colon organoids and healthy mice. Our findings strongly encourage further translational studies to evaluate KAN0438757 in CRC therapy.

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Section: Discussionmentioning

confidence: 81%

Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo

Oliveira

Goldhardt

Edelmann

et al. 2021

Cancers

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“…However, there has yet to be a clear consensus regarding the effect of oxaliplatin on steatosis, especially in light of findings such as that of Lu and colleagues, who showed that oxaliplatin aggravates existing steatosis in a non-alcoholic fatty liver disease mouse model [27]. More widely accepted is the association of CASH with irinotecan-based chemotherapies, which were not explored in the present study but would be highly pertinent for future investigations [28].…”

Section: Discussionmentioning

confidence: 82%

Evaluation of Adjuvant Chemotherapy-Associated Steatosis (CAS) in Colorectal Cancer

et al. 2021

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Chemotherapy-associated steatosis is poorly understood in the context of colorectal cancer. In this study, Stage II–III colorectal cancer patients were retrospectively selected to evaluate the frequency of chemotherapy-associated steatosis and to determine whether patients on statins throughout adjuvant chemotherapy develop chemotherapy-associated steatosis at a lower frequency. Baseline and incident steatosis for up to one year from chemotherapy start date was assessed based on radiology. Of 269 patients, 76 (28.3%) had steatosis at baseline. Of the remaining 193 cases, patients receiving adjuvant chemotherapy (n = 135) had 1.57 (95% confidence interval [CI], 0.89 to 2.79) times the adjusted risk of developing steatosis compared to patients not receiving chemotherapy (n = 58). Among patients who underwent chemotherapy, those using statins for pre-existing hyperlipidemia (n = 37) had 0.71 (95% CI, 0.10 to 2.75) times the risk of developing steatosis compared to patients who were not prevalent users of statins (n = 98). Chemotherapeutic treatment of Stage II–III colorectal cancer appears to be consistent with a moderately increased risk of steatosis, although larger studies are necessary to assess the significance of this observation. Prospective trials should be considered to further explore the potential for protective use of statins in this curative patient population.

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“…This may trigger an inflammatory reaction leading to steatohepatitis, and in turn to fibrosis and cirrhosis. Sinusoidal obstruction syndrome is a separate entity with direct toxicity to LSEC leading to occlusive phenomena in the sinusoids[ 407 ].…”

Section: Section 8: Liver Regeneration: Implications For Therapy Of Liver Tumoursmentioning

confidence: 99%

Liver regeneration biology: Implications for liver tumour therapies

Hadjittofi¹,

Feretis²,

Martin³

et al. 2021

WJCO

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The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.

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Chemotherapy-associated liver injury in colorectal cancer

Cited by 32 publications

References 68 publications

Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo

Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo

Evaluation of Adjuvant Chemotherapy-Associated Steatosis (CAS) in Colorectal Cancer

Liver regeneration biology: Implications for liver tumour therapies

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