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Nanometronomic treatment of 4T1 breast cancer with nanocaged doxorubicin prevents drug resistance and circumvents cardiotoxicity.

ABSTRACT: Chemotherapeutic treatment of breast cancer is based on maximum tolerated dose (MTD) approach. However, advanced stage tumors are not effectively eradicated by MTD owing to suboptimal drug targeting, onset of therapeutic resistance and neoangiogenesis. In contrast, "metronomic" chemotherapy is based on frequent drug administrations at lower doses, resulting in neovascularization inhibition and induction of tumor dormancy. Here we show the potential of H-ferritin (HFn)-mediated targeted nanodelivery of metronomic doxorubicin (DOX) in the setting of a highly aggressive and metastatic 4T1 breast cancer mouse model with DOX-inducible expression of chemoresistance. We find that HFn-DOX administered at repeated doses of 1.24 mg kg-1 strongly improves the antitumor potential of DOX chemotherapy arresting the tumor progression. We find that such a potent antitumor effect is attributable to multiple nanodrug actions beyond cell killing, including inhibition of tumor angiogenesis and avoidance of chemoresistance. Multiparametric assessment of heart tissues, including histology, ultrastructural analysis of tissue morphology, and measurement of markers of reactive oxygen species and hepatic/renal conditions, provided evidence that metronomic HFn-DOX allowed us to overcome cardiotoxicity. Our results suggest that HFn-DOX has tremendous potential for the development of "nanometronomic" chemotherapy toward safe and tailored oncological treatments.

SUBMITTER: Mazzucchelli S

PROVIDER: S-EPMC5352408 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Nanometronomic treatment of 4T1 breast cancer with nanocaged doxorubicin prevents drug resistance and circumvents cardiotoxicity.

Mazzucchelli Serena S Bellini Michela M Fiandra Luisa L Truffi Marta M Rizzuto Maria A MA Sorrentino Luca L Longhi Erika E Nebuloni Manuela M Prosperi Davide D Corsi Fabio F

Oncotarget 20170101 5

Chemotherapeutic treatment of breast cancer is based on maximum tolerated dose (MTD) approach. However, advanced stage tumors are not effectively eradicated by MTD owing to suboptimal drug targeting, onset of therapeutic resistance and neoangiogenesis. In contrast, "metronomic" chemotherapy is based on frequent drug administrations at lower doses, resulting in neovascularization inhibition and induction of tumor dormancy. Here we show the potential of H-ferritin (HFn)-mediated targeted nanodeliv ...[more]

PMID: 28039473

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Project description:BackgroundCyclic nucleotides play critical roles in cardiovascular biology and disease. PDE10A (phosphodiesterase 10A) is able to hydrolyze both cAMP and cGMP. PDE10A expression is induced in various human tumor cell lines, and PDE10A inhibition suppresses tumor cell growth. Chemotherapy drug such as doxorubicin (DOX) is widely used in chemotherapy. However, cardiotoxicity of DOX remains to be a serious clinical complication. In the current study, we aim to determine the role of PDE10A and the effect of PDE10A inhibition on cancer growth and cardiotoxicity induced by DOX.MethodsWe used global PDE10A knockout (KO) mice and PDE10A inhibitor TP-10 to block PDE10A function. DOX-induced cardiotoxicity was evaluated in C57Bl/6J mice and nude mice with implanted ovarian cancer xenografts. Isolated adult mouse cardiomyocytes and a human ovarian cancer cell line were used for in vitro functional and mechanistic studies.ResultsWe found that PDE10A deficiency or inhibition alleviated DOX-induced myocardial atrophy, apoptosis, and dysfunction in C57Bl/6J mice. RNA sequencing study revealed a number of PDE10A-regulated signaling pathways involved in DOX-induced cardiotoxicity. PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX on various human cancer cells. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protecting DOX-induced cardiotoxicity. In isolated cardiomyocytes, PDE10A contributed to DOX-induced cardiomyocyte death via increasing Top2β (topoisomerase 2β) expression, mitochondrial dysfunction, and DNA damage by antagonizing cGMP/PKG (protein kinase G) signaling. PDE10A contributed to cardiomyocyte atrophy via potentiating FoxO3 (forkhead box O3) signaling via both cAMP/PKA (protein kinase A)- and cGMP/PKG-dependent signaling.ConclusionsTaken together, our study elucidates a novel role for PDE10A in cardiotoxicity induced by DOX and cancer growth. Given that PDE10A has been already proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy in cancer therapy, with effects preventing DOX-induced cardiotoxicity and simultaneously antagonizing cancer growth.

Dataset Information

Nanometronomic treatment of 4T1 breast cancer with nanocaged doxorubicin prevents drug resistance and circumvents cardiotoxicity.

Publications

Nanometronomic treatment of 4T1 breast cancer with nanocaged doxorubicin prevents drug resistance and circumvents cardiotoxicity.

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