Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice

Abstract

Doxorubicin is the chemotherapeutic drug of choice for a wide variety of cancers, and cardiotoxicity is one of the major side effects of doxorubicin treatment. One of the main cellular targets of doxorubicin in the heart is mitochondria. Mitochondrial sirtuin, SIRT3 has been shown to protect against doxorubicin-induced cardiotoxicity. We have recently identified honokiol (HKL) as an activator of SIRT3, which protects the heart from developing pressure overload hypertrophy. Here, we show that HKL-mediated activation of SIRT3 also protects the heart from doxorubicin-induced cardiac damage without compromising the tumor killing potential of doxorubicin. Doxorubicin-induced cardiotoxicity is associated with increased ROS production and consequent fragmentation of mitochondria and cell death. HKL-mediated activation of SIRT3 prevented Doxorubicin induced ROS production, mitochondrial damage and cell death in rat neonatal cardiomyocytes. HKL also promoted mitochondrial fusion. We also show that treatment with HKL blocked doxorubicin-induced cardiac toxicity in mice. This was associated with reduced mitochondrial DNA damage and improved mitochondrial function. Furthermore, treatments of mice, bearing prostrate tumor-xenografts, with HKL and doxorubicin showed inhibition of tumor growth with significantly reduced cardiac toxicity. Our results suggest that HKL-mediated activation of SIRT3 protects the heart from doxorubicin-induced cardiotoxicity and represents a potentially novel adjunct for chemotherapy treatments.

SIRT3 activator honokiol ameliorates surgery/anesthesia‐induced cognitive decline in mice through anti‐oxidative stress and anti‐inflammatory in hippocampus

“…Recent studies showed that SIRT3 exhibits mighty deacetylase activity and is the key regulator in organ protection under many pathologic states including inflammatory and oxidative stress, acting pivotal roles in development and progression of metabolic diseases including diabetes, neurodegenerative disorders, and other diseases . Honokiol (HNK), [2‐(4‐hydroxy‐3‐prop‐2‐enyl‐phenyl)‐4‐prop‐2‐enyl‐phenol], is a bioactive compound obtained from Magnolia grandiflora which possesses multiple properties including anti‐tumor, anti‐arrhythmic, anti‐thrombocytic, anti‐inflammatory, anti‐angiogenesis, anxiolytic, anti‐oxidative activities in vivo and in vitro . As a potent reactive oxygen species (ROS) scavenger, it is also reported that HNK can enhance the overexpression of SIRT3 to improve antioxidant activity and mitochondrial energy regulation thereby reducing the levels of Aβ and sAPPβ in Chinese Hamster Ovarian (CHO) cells .…”

“…[12][13][14][15] Honokiol (HNK), [2-(4- anti-oxidative activities in vivo and in vitro. [16][17][18][19][20][21] As a potent reactive oxygen species (ROS) scavenger, it is also reported that HNK can enhance the overexpression of SIRT3 to improve antioxidant activity and mitochondrial energy regulation thereby reducing the levels of Aβ and sAPPβ in Chinese Hamster Ovarian (CHO) cells. 22 Additionally, Xian et al suggested that HNK could improve learning and memory impairments induced by scopolamine in mice and attenuate the concentration of prostaglandin E2 and cyclooxygenase-2 level and the neuroinflammatory processes.…”

Mitochondrial Dysfunction Associated with Doxorubicin

“…One study has reported that SIRT-3 is decreased by DOX treatment due to the rise in ROS production and mitochondrial dysfunction. So, reducing SIRT-3 leads to elevation to ROS and HIF1α stabilization, which is an essential factor to shift metabolism from β-oxidation of fatty acid to glycolysis (the Warburg effect) [85]. Further, the inhibition of protein or slicing of the HIF1α gene has been suggested to decrease drug resistance against DOX [86].…”

Changes in the Expression and the Role of Sirtuin 3 in Cancer Cells and in Cardiovascular Health and Disease

“…Honokiol, which is a polyphenol derived from magnolia tree, lessens cardiac hypertrophy and fibrosis by activating SIRT3 and protects cardiomyocytes from doxorubicin-induced cell destruction and death by promoting mitochondrial fusion and limiting mitochondrial ROS levels and mtDNA damage [99,100]. Adenovirus-mediated overexpression of SIRT3 might decrease pathogenesis of cardiovascular diseases by inhibition of Dox-induced cardiac hypertrophy and mitochondrial defects.…”