A clinically relevant combination treatment with doxorubicin and cyclophosphamide does not induce hepatotoxicity in C57BL/6J mice

Pondugula, Satyanarayana R.; Salamat, Julia M.; Abbott, Kodye L.; Flannery, Patrick; Majrashi, Mohammed; Almaghrabi, Mohammed; Govindarajulu, Manoj; Ramesh, Sindhu; Sandey, Maninder; Onteru, Suneel Kumar; Huang, Chen-Che Jeff; Iwaki, Yoshimi; Gill, Kristina; Narayanan, N. Hari; McElroy, Edwin; Desai, Darshini; Nadar, Rishi M.; Moore, Timothy; Dhanasekaran, Muralikrishnan

doi:10.1016/j.livres.2021.04.002

Cited by 6 publications

(4 citation statements)

References 19 publications

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“…As in the heart, activation of TGFβ1 receptors in the liver leads to differentiation of HSCs into myofibroblasts, hepatocyte cell death, and fibrosis. 61 These data are consistent with isolated reports from the literature indicating that co-administration of doxorubicin with immunosuppressive drugs such as cyclophosphamide 62 or prednisolone, 63 which antagonize TGFβ1, 64 protects the liver from doxorubicin-induced damage, a result that can also be achieved via inhibition of RGS7-driven TGFβ1 production.…”

Section: Discussionsupporting

confidence: 88%

Cardiac RGS7 and RGS11 drive TGFβ1‐dependent liver damage following chemotherapy exposure

et al. 2023

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Off target damage to vital organ systems is an unfortunate side effect of cancer chemotherapy and remains a major limitation to the use of these essential drugs in the clinic. Despite decades of research, the mechanisms conferring susceptibility to chemotherapy driven cardiotoxicity and hepatotoxicity remain unclear. In the livers of patients with a history of chemotherapy, we observed a twofold increase in expression of G protein regulator RGS7 and a corresponding decrease in fellow R7 family member RGS11. Knockdown of RGS7 via introduction of RGS7 shRNA via tail vein injection decreased doxorubicin‐induced hepatic collagen and lipid deposition, glycogen accumulation, and elevations in ALT, AST, and triglycerides by approximately 50%. Surprisingly, a similar result could be achieved via introduction of RGS7 shRNA directly to the myocardium without impacting RGS7 levels in the liver directly. Indeed, doxorubicin‐treated cardiomyocytes secrete the endocrine factors transforming growth factor β1 (TGFβ1) and TGFβ superfamily binding protein follistatin‐related protein 1 (FSTL1). Importantly, RGS7 overexpression in the heart was sufficient to recapitulate the impacts of doxorubicin on the liver and inhibition of TGFβ1 signaling with the receptor blocker GW788388 ameliorated the effect of cardiac RGS7 overexpression on hepatic fibrosis, steatosis, oxidative stress, and cell death as well as the resultant elevation in liver enzymes. Together these data demonstrate that RGS7 controls both the release of TGFβ1 from the heart and the profibrotic and pro‐oxidant actions of TGFβ1 in the liver and emphasize the functional significance of endocrine cardiokine signaling in the pathogenesis of chemotherapy drive multiorgan damage.

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Section: Discussionsupporting

confidence: 88%

Cardiac RGS7 and RGS11 drive TGFβ1‐dependent liver damage following chemotherapy exposure

et al. 2023

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“…However, there is limited literature available on chemotherapy treatments for mammary tumors in guinea pigs. In a study by Pondugula et al [25], they reported the safest doses of doxorubicin (2mg/kg) and cyclophosphamide (50mg/kg) for mice. These doses are currently used in other rodent species, such as guinea pigs.…”

Section: Discussionmentioning

confidence: 99%

Mammary tubular carcinoma in a guinea pig (Cavia porcellus): case report

Oliveira

Dalmagro³

et al. 2023

BJCR

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Mammary carcinomas are common malignant tumors encompassing the main diagnostic mammary gland tumor cause in female dogs and cats. Few reports in wild animals are, however, available. In this context, this study aimed to characterize the clinical and histological aspects of a mammary tubular carcinoma case in a guinea pig (Cavia porcellus). A four-year-old non-spayed female guinea pig was seen at a veterinary clinic in the municipality of Natal, Rio Grande do Norte, Brazil. Upon clinical examination, the animal was active, with a normal body condition, weighing 660 grams, hydrated, and presenting normal-colored mucous membranes. Increased left breast volume was observed, about 3.5 cm in diameter, non-adherent and with an ulcerated surface located medially to the mammary papilla, about 1.8 cm in diameter. The observed clinical findings indicated a presumptive neoplastic lesion diagnosis. A unilateral mastectomy was performed (left breast) and breast tissue fragments were histologically evaluated, confirming the tubular mammary carcinoma diagnosis. The surgical procedure and post-surgical treatment recommended in this report were proven efficient. Knowledge of diseases that affect non-conventional pets, such as the tubular mammary carcinoma reported herein, is paramount in improving the quality of life of these animals.

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“…33 Therefore, in this study, molecular docking of doxorubicin and pyrazoline B was performed and compared to the synergistic effect of cyclophosphamide-doxorubicin, which has been proven to have anticancer effects and does not induce hepatotoxicity. 27 Blind 2A show that pyrazoline B binds to the DNA-binding site of topoisomerase I in a non-competitive manner with doxorubicin, similar to cyclophosphamide (Figure 2B). Doxorubicin, pyrazoline B, and cyclophosphamide have binding affinity of -8.4, -7.0, and -5.1 kcal/mol, respectively (Table 7).…”

Section: Molecular Docking Studymentioning

confidence: 97%

“…Protein and ligand visualizations were performed using the UCSF chimera 24 and ligplot plus. 26 The in silico synergistic effect of cyclophosphamide-doxorubicin 27 on topoisomerase I and II and ascorbic acid-paclitaxel 28 on α-β tubulin and Bcl2 was used as positive controls because the drug combination has been proven to have anticancer effects in vitro and in vivo.…”

Section: Ligand-protein Dockingmentioning

confidence: 99%

Pyrazoline B-Paclitaxel or Doxorubicin Combination Drugs Show Synergistic Activity Against Cancer Cells: In silico Study

Wiraswati,

Bashari,

Alfarafisa

et al. 2024

AABC

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Background: Multidrug resistance in various cancer types is a major obstacle in cancer treatment. The concept of a single drug molecular target often causes treatment failure due to the complexity of the cellular processes. Therefore, combination chemotherapy, in which two or more anticancer drugs are co-administered, can overcome this problem because it potentially have synergistic efficacy besides reducing resistance, and drug doses. Previously, we reported that pyrazoline B had promising anticancer activity in both in silico and in vitro studies. To increase the efficacy of this drug, co-administration with established anticancer drugs such as doxorubicin and paclitaxel is necessary. Materials and Methods:In this study, we used an in silico approach to predict the synergistic effect of pyrazoline B with paclitaxel or doxorubicin using various computational frameworks and compared the results with those of an established study on the combination of doxorubicin-cyclophosphamide and paclitaxel-ascorbic acid. Results and Discussion: Drug interaction analysis showed the combination was safe with no contraindications or side effects. Furthermore, molecular docking studies revealed that doxorubicin-pyrazoline B and doxorubicin-cyclophosphamide may synergistically inhibit cancer cell proliferation by inhibiting the binding of topoisomerase I to the DNA chain. Moreover, the combination of pyrazoline B-paclitaxel may has synergistic activity to cause apoptosis by inhibiting Bcl2 binding to the Bax fragment or inhibiting cell division by inhibiting α-β tubulin disintegration. Paclitaxel-ascorbic acid had a synergistic effect on the inhibition of α-β tubulin disintegration. Conclusion:The results show that this combination is promising for further in vitro and in vivo studies.

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A clinically relevant combination treatment with doxorubicin and cyclophosphamide does not induce hepatotoxicity in C57BL/6J mice

Cited by 6 publications

References 19 publications

Cardiac RGS7 and RGS11 drive TGFβ1‐dependent liver damage following chemotherapy exposure

Cardiac RGS7 and RGS11 drive TGFβ1‐dependent liver damage following chemotherapy exposure

Mammary tubular carcinoma in a guinea pig (Cavia porcellus): case report

Pyrazoline B-Paclitaxel or Doxorubicin Combination Drugs Show Synergistic Activity Against Cancer Cells: In silico Study

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