Base excision repair imbalance in colorectal cancer has prognostic value and modulates response to chemotherapy Base excision repair imbalance in colorectal cancer has prognostic value and modulates response to chemotherapy

Doxorubicin (DOX)-induced cardiotoxicity in chemotherapy is a major treatment drawback. Clinical trials on the cardioprotective effects of exercise in cancer patients have not yet been published. Thus, we conducted a systematic review and meta-analysis of preclinical studies for to assess the efficacy of exercise training on DOX-induced cardiomyopathy. We included studies with animal models of DOX-induced cardiomyopathy and exercise training from PubMed, Web of Sciences and Scopus databases. The outcome was the mean difference (MD) in fractional shortening (FS, %) assessed by echocardiography between sedentary and trained DOX-treated animals. Trained DOX-treated animals improved 7.40% (95% CI 5.75–9.05, p < 0.001) in FS vs. sedentary animals. Subgroup analyses revealed a superior effect of exercise training execution prior to DOX exposure (MD = 8.20, 95% CI 6.27–10.13, p = 0.010). The assessment of cardiac function up to 10 days after DOX exposure and completion of exercise protocol was also associated with superior effect size in FS (MD = 7.89, 95% CI 6.11–9.67, p = 0.020) vs. an echocardiography after over 4 weeks. Modality and duration of exercise, gender and cumulative DOX dose did were not individually associated with changes on FS. Exercise training is a cardioprotective approach in rodent models of DOX-induced cardiomyopathy. Exercise prior to DOX exposure exerts greater effect sizes on FS preservation.

Despite the ample improvements of CRC molecular landscape, the therapeutic options still rely on conventional chemotherapy-based regimens for early disease, and few targeted agents are recommended for clinical use in the metastatic setting. Moreover, the impact of cytotoxic, targeted agents, and immunotherapy combinations in the metastatic scenario is not fully satisfactory, especially the outcomes for patients who develop resistance to these treatments need to be improved. Here, we examine the opportunity to consider therapeutic agents targeting DNA repair and DNA replication stress response as strategies to exploit genetic or functional defects in the DNA damage response (DDR) pathways through synthetic lethal mechanisms, still not explored in CRC. These include the multiple actors involved in the repair of DNA double-strand breaks (DSBs) through homologous recombination (HR), classical non-homologous end joining (NHEJ), and microhomology-mediated end-joining (MMEJ), inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP), as well as inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM). We also review the biomarkers that guide the use of these agents, and current clinical trials with targeted DDR therapies.

To evaluate the effect of preventive aerobic exercise training on sympathovagal function, cardiac function, and DNA repair capacity in a preclinical model of doxorubicin (DOX)-induced cardiomyopathy. Forty male Wistar-Kyoto rats were allocated into four groups (n = 10/group): D (DOX-treated) and C (controls) remained sedentary, and DT (DOX-trained) and CT (control-trained) performed aerobic training 4 days/week, during 4 weeks before exposure to DOX (4 mg/kg/week during 4 weeks) or saline solution. We evaluated cardiac function (echocardiography), hemodynamic and sympathovagal modulation (artery-femoral cannulation), cardiac troponin T levels, and DNA repair capacity (comet assay). Exercise training preserved ejection fraction (D: − 14.44% vs. DT: − 1.05%, p < 0.001), fractional shortening (D: − 8.96% vs. DT: − 0.27%, p = 0.025) and troponin T levels (D: 6.4 ± 3.6 vs. DT: 2.8 ± 1.7 ng/mL, p = 0.010). DOX increased heart rate variability (C: 27.7 ± 7.9 vs. D: 7.5 ± 2.2 ms², p < 0.001) and induced sympathovagal dysfunction (LF/HF, C: 0.37 ± 0.15 vs. D: 0.15 ± 0.15, p = 0.036) through exacerbation of sympathetic function (LF, C: 0.22 ± 0.01 vs. D: 0.48 ± 0.24 Hz, p = 0.019). Peripheral mononuclear blood cells of DT animals presented lower residual DNA damage (D: 43.4 ± 8.4% vs. DT: 26 ± 3.4%, p = 0.003 after 1 h). Cardioprotective effects of preventive aerobic exercise training are mediated by preservation of sympathovagal function and improvement of DNA repair capacity of peripheral blood mononuclear cells.

Although anthracycline (ANT)-based treatment strongly contributes to cancer survivorship, the use of these agents is limited by the risk of induced cardiomyopathy. For those patients who develop heart failure, myocardial regenerative approaches are of particular interest, and a growing body of preclinical studies have been investigating the use of cell therapy for ANT-induced cardiomyopathy (AIC). However, since animal models and modalities of cell therapy are highly heterogeneous between studies, the efficacy of cell therapy for AIC is not clear. Thus, we conducted a systematic review and meta-analysis of experimental studies reporting the use of cell therapy with mesenchymal stromal cells (MSC) or bone marrow mononuclear cells (BMMNC) in animal models of AIC with regard to cardiac function. The Medline, EMBASE and Web of Science databases were searched from inception to November 2019. Two reviewers independently extracted data on study quality and the results regarding left ventricle ejection fraction (LVEF) and fractional shortening (FS). The quality of outcomes was evaluated using the Cochrane, CAMARADES and SYRCLE bias risk tools. Pooled random-effects modelling was used to calculate pooled mean differences (MD) and 95% confidence intervals (CI). Twenty-two studies comprising 381 small animals (rabbits and rodents) were included. A pooled meta-analysis of all treatments showed that cell therapy increased LVEF by 9.87% (95% CI, 7.25-12.50, p<0.00001) and FS by 7.80% (95% CI, 5.68-9.92, p<0.00001) in small animals with AIC. Cell therapy with MSC/BMMNC is effective to mitigate the deleterious effects of ANT on cardiac function in preclinical models. Nevertheless, due to the small number of studies and considerable heterogeneity, future translational studies must be designed to diminish between-study discrepancies and increase similarity to the clinical landscape.