Atypical G Protein β5 Promotes Cardiac Oxidative Stress, Apoptosis, and Fibrotic Remodeling in Response to Multiple Cancer Chemotherapeutics.
TL;DR: The experiments suggest that inhibition of Gβ5 might represent a novel means to circumvent cardiotoxicity in cancer patients whose treatment regimens include anthracyclines, taxanes, or fluoropyrimidines.
Abstract: The clinical use of multiple classes of cancer chemotherapeutics is limited by irreversible, dose-dependent, and sometimes life-threatening cardiotoxicity. Though distinct in their mechanisms of action, doxorubicin, paclitaxel, and 5-FU all induce rapid and robust upregulation of atypical G protein Gβ5 in the myocardium correlating with oxidative stress, myocyte apoptosis, and the accumulation of proinflammatory and profibrotic cytokines. In ventricular cardiac myocytes (VCM), Gβ5 deficiency provided substantial protection against the cytotoxic actions of chemotherapeutics, including reductions in oxidative stress and simultaneous attenuation of ROS-dependent activation of the ATM and CaMKII proapoptotic signaling cascades. In addition, Gβ5 loss allowed for maintenance of Δψm, basal mitochondrial calcium uniporter expression, and mitochondrial Ca2+ levels, effects likely to preserve functional myocyte excitation-contraction coupling. The deleterious effects of Gβ5 are not restricted to VCM, however, as Gβ5 knockdown also reduces chemotherapy-induced release of proinflammatory cytokines (e.g., TNFα), hypertrophic factors (e.g., ANP), and profibrotic factors (e.g., TGFβ1) from both VCM and ventricular cardiac fibroblasts, with the most dramatic reduction occurring in cocultured cells. Our experiments suggest that Gβ5 facilitates the myofibroblast transition, the persistence of which contributes to pathologic remodeling and heart failure. The convergence of Gβ5-mediated, ROS-dependent signaling pathways in both cell types represents a critical etiological factor in the pathogenesis of chemotherapy-induced cardiotoxicity. Indeed, intracardiac injection of Gβ5-targeted shRNA allowed for heart-specific protection against the damaging impact of chronic chemotherapy. Together, our results suggest that inhibition of Gβ5 might represent a novel means to circumvent cardiotoxicity in cancer patients whose treatment regimens include anthracyclines, taxanes, or fluoropyrimidines.Significance: These findings suggest that inhibiting an atypical G-protein might provide a strategy to limit the cardiotoxicity in cancer patients treated with anthracyclines, taxanes, or fluoropyrimidines. Cancer Res; 78(2); 528-41. ©2017 AACR.
Citations
More filters
TL;DR: The mechanism of action of OS in cardiacoxicity of antineoplastic drugs is reviewed to provide new ideas for researchers, and provide further guidance for clinical prevention and treatment of cardiac toxicity of anti-tumor drugs in the future.
15 citations
TL;DR: Melatonin has been shown to have cardioprotective activity in multiple animal and human studies and is effective in suppressing heart damage mediated by pharmacologic drugs.
Abstract: The pineal gland is a neuroendocrine gland which produces melatonin, a neuroendocrine hormone with critical physiological roles in the circadian rhythm and sleep-wake cycle. Melatonin has been shown to possess anti-oxidant activity and neuroprotective properties. Numerous studies have shown that melatonin has significant functions in cardiovascular disease, and may have anti-aging properties. The ability of melatonin to decrease primary hypertension needs to be more extensively evaluated. Melatonin has shown significant benefits in reducing cardiac pathology, and preventing the death of cardiac muscle in response to ischemia-reperfusion in rodent species. Moreover, melatonin may also prevent the hypertrophy of the heart muscle under some circumstances, which in turn would lessen the development of heart failure. Several currently used conventional drugs show cardiotoxicity as an adverse effect. Recent rodent studies have shown that melatonin acts as an anti-oxidant and is effective in suppressing heart damage mediated by pharmacologic drugs. Therefore, melatonin has been shown to have cardioprotective activity in multiple animal and human studies. Herein, we summarize the most established benefits of melatonin in the cardiovascular system with a focus on the molecular mechanisms of action.
14 citations
TL;DR: A CSP3 conjugated liposome drug delivery system containing doxorubicin (DOX) and microRNA101 (miR101) expression plasmids (CSP3-Lipo-DOX-miR 101) showed that the system demonstrated significantly enhanced cytotoxicity to SiHa cells and DOX resistant Si Ha cells, SiHa/ADR.
Abstract: 'Targeting peptides' have demonstrated their value in diagnostic imaging and therapy and novel peptide probes specific to cervical cancer were developed. In the M13KE phage dodecapeptide (12-mer) peptide library, the phage clone S7 showed the best binding to the cancer cells as confirmed by immunofluorescence and flow cytometry assays, and was selected for continued studies. Its binding peptide, CSP3, was synthesized from the sequence of S7's 12-mer at the N-terminus of the minor coat protein pIII of this M13KE phage vector. The peptide's binding was analyzed by the same assays used for S7. It was also assessed using competitive inhibition and binding to a tissue chip. The results demonstrated that the CSP3 peptide bound to cervical carcinoma cells with high sensitivity and specificity. The positive results indicated that the peptide CSP3, conjugated with nanomaterials and chemotherapeutics, may be developed as a targeting vehicle for therapeutic drug delivery against cervical cancer, especially cervical cancer with multiple drug resistance. For this aim, we prepared a CSP3 conjugated liposome drug delivery system containing doxorubicin (DOX) and microRNA101 (miR101) expression plasmids (CSP3-Lipo-DOX-miR101), and the primary result showed that the system demonstrated significantly enhanced cytotoxicity to SiHa cells and DOX resistant SiHa cells, SiHa/ADR. Our results showed that CSP3 is a cervical cancer targeting 12aa peptide with high specificity and sensitivity, and the CSP3 conjugated drug delivery system, CSP3-Lipo-DOX-miR101 has promising potential for development as an efficient drug system for the therapy of cervical cancer.
13 citations
TL;DR: In this article , Boc protected tyrosine-tryptophan dipeptide-based nanoparticles (DPNPs) with structure rigidification by Zn(ii), which shifted the peptide's intrinsic fluorescent properties from the ultraviolet to the visible range.
Abstract: Self-assembled peptide-based nanostructures, comprised of naturally occurring amino acids, display excellent biocompatibility, biodegradability, flexible responsiveness, and synthetic feasibility and can be customized for various biomedical applications. However, the lack of inherent optical properties of peptide-based nanoparticles is a limitation on their use as imaging probes or drug delivery vehicles. To overcome this impediment, we generated Boc protected tyrosine–tryptophan dipeptide-based nanoparticles (DPNPs) with structure rigidification by Zn(ii), which shifted the peptide's intrinsic fluorescent properties from the ultraviolet to the visible range. These DPNPs are photostable, biocompatible and have visible fluorescence signals that allow for real-time monitoring of their entry into cells. We further show that two DPNPs (PS1-Zn and PS2-Zn) can encapsulate the chemotherapeutic drug doxorubicin (Dox) and facilitate intracellular drug delivery resulting in cancer cell killing actions comparable to the unencapsulated drug. Finally, we chemically modified our DPNPs with an aptamer directed toward the epithelial cell surface marker EPCAM, which improved Dox delivery to the lung cancer epithelial cell line A549. In contrast, the aptamer conjugated DPNPs failed to deliver Dox into the cardiomyocyte cell line AC16. Theoretically, this strategy could be employed in vivo to specifically deliver Dox to cancer cells while sparing the myocardium, a major source of dose-limiting adverse events in the clinic. Our work represents an important proof-of-concept exercise demonstrating that ultra-short peptide-based fluorescent nanostructures have great promise for the development of new imaging probes and targeted drug delivery vehicles.
9 citations
01 Jul 2014
TL;DR: In this article, the impact of p53 inhibition on acute vs. late-stage DOX cardiotoxicity was examined in a juvenile model, where two-week-old MHC-CB7 mice and their non-transgenic (NON-TXG) littermates received weekly DOX injections for 5 weeks (25 mg/kg cumulative dose).
Abstract: Aims Doxorubicin (DOX) is an effective anti-cancer therapeutic, but is associated with both acute and late-stage cardiotoxicity. Children are particularly sensitive to DOX-induced heart failure. Here, the impact of p53 inhibition on acute vs. late-stage DOX cardiotoxicity was examined in a juvenile model.
Methods and results Two-week-old MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes) and their non-transgenic (NON-TXG) littermates received weekly DOX injections for 5 weeks (25 mg/kg cumulative dose). One week after the last DOX treatment (acute stage), MHC-CB7 mice exhibited improved cardiac function and lower levels of cardiomyocyte apoptosis when compared with the NON-TXG mice. Surprisingly, by 13 weeks following the last DOX treatment (late stage), MHC-CB7 exhibited a progressive decrease in cardiac function and higher rates of cardiomyocyte apoptosis when compared with NON-TXG mice. p53 inhibition blocked transient DOX-induced STAT3 activation in MHC-CB7 mice, which was associated with enhanced induction of the DNA repair proteins Ku70 and Ku80. Mice with cardiomyocyte-restricted deletion of STAT3 exhibited worse cardiac function, higher levels of cardiomyocyte apoptosis, and a greater induction of Ku70 and Ku80 in response to DOX treatment during the acute stage when compared with control animals.
Conclusion These data support a model wherein a p53-dependent cardioprotective pathway, mediated via STAT3 activation, mitigates DOX-induced myocardial stress during drug delivery. Furthermore, these data suggest an explanation as to how p53 inhibition can result in cardioprotection during drug treatment and, paradoxically, enhanced cardiotoxicity long after the cessation of drug treatment.
7 citations
References
More filters
TL;DR: Fixed-time assay measuring H 2 O 2 consumption and continuous monitoring of Glutathione disulfide (GSSG) formation are cited here.
Abstract: Publisher Summary To determine glutathione peroxidase reliably, some factors of potential pitfall have to be considered, for example, enzymatic side reactions of substrates (especially when crude tissue samples are assayed), high and variable spontaneous reaction rates of substrates, and the peculiar kinetics of the enzyme itself. With the best documented example, the enzyme of bovine red blood cells, ping-pong kinetics with infinite limiting maximum velocities, and Michaelis constants have been established. This means that the generally recommended conditions for determination of enzyme activity––that is, “saturating” concentrations of all substrates, cannot possibly be fulfilled. In consequence, compromises are inevitable in the choice of substrate concentration for the assay and in the definition of the unit of activity. Fixed-time assay measuring H 2 O 2 consumption and continuous monitoring of Glutathione disulfide (GSSG) formation are cited here. The main differences between the assay procedure described and those proposed by others are listed in the chapter. To compare the results obtained by different procedures, appropriate empirical converting factors are also given.
4,341 citations
"Atypical G Protein β5 Promotes Card..." refers methods in this paper
...GPX activity was measured using the method of Flohe and Gunzler(30)....
[...]
TL;DR: An overview of issues confirms that anthracyclines remain “evergreen” drugs with broad clinical indications but have still an improvable therapeutic index.
Abstract: The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.
3,320 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...Gβ5 promotes chemotherapeutic-induced activation of DNA damage signaling– Multiple apoptotic signaling cascades are believed to mediate ROS-induced cardiac damage including the ATM/p53 pathway(32)....
[...]
TL;DR: A critical analysis of the challenges and limitations of the most widely used fluorescent probes for detecting and measuring reactive oxygen and nitrogen species and proposed guidelines that will help present and future researchers with regard to the optimal use of selected fluorescent probes and interpretation of results are presented.
1,423 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...Because there are several limitations to the use of CM-H2DCFDA fluorescent probes in detecting total ROS from cells or tissue(31), amongst them an inability to differentiate between the various reactive species, we extended our analysis of Gβ5-dependent ROS generation to include direct measurement of H2O2....
[...]
TL;DR: It is shown that oxidation of paired regulatory domain methionine residues sustains CaMKII activity in the absence of Ca2+/CaM and highlights the critical importance of oxidation-dependent CaMK II activation to AngII and ischemic myocardial apoptosis.
989 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...The pro-apoptotic actions of ATM and CaMKII following chemotherapy exposure require Gβ5and ROS– Based on the recent emergence of oxidative mechanisms of activation for both CaMKII(35) and ATM(36), we suspected that the ability of Gβ5 to promote activation of both kinases required Gβ5-dependent ROS generation....
[...]
...Because it was recently discovered that CaMKII can be directly activated by oxidation of the enzyme’s regulatory domain(35), we hypothesized that the link between Gβ5 and mitochondria might lie in ROS-dependent CaMKII activation....
[...]
TL;DR: It is shown that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex, and that ATM is an important sensor of reactive oxygen species in human cells.
Abstract: The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide-cross-linked dimer, and mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway. Identification of this pathway explains observations of ATM activation under conditions of oxidative stress and shows that ATM is an important sensor of reactive oxygen species in human cells.
955 citations
"Atypical G Protein β5 Promotes Card..." refers background in this paper
...The pro-apoptotic actions of ATM and CaMKII following chemotherapy exposure require Gβ5and ROS– Based on the recent emergence of oxidative mechanisms of activation for both CaMKII(35) and ATM(36), we suspected that the ability of Gβ5 to promote activation of both kinases required Gβ5-dependent ROS generation....
[...]