SIRT1 activation and its effect on intercalated disc proteins as a way to reduce doxorubicin cardiotoxicity

Abstract

According to the World Health Organization, the neoplasm is one of the main reasons for morbidity and mortality worldwide. At the same time, application of cytostatic drugs like an independent type of cancer treatment and in combination with surgical methods, is often associated with the development of cardiovascular complications both in the early and in the delayed period of treatment. Doxorubicin (DOX) is the most commonly used cytotoxic anthracycline antibiotic. DOX can cause both acute and delayed side effects. The problem is still not solved, as evidenced by the continued activity of researchers in terms of developing approaches for the prevention and treatment of cardiovascular complications. It is known, the heart muscle consists of cardiomyocytes connected by intercalated discs (ID), which ensure the structural, electrical, metabolic unity of the heart. Various defects in the ID proteins can lead to the development of cardiovascular diseases of various etiologies, including DOX-induced cardiomyopathy. The search for ways to influence the functioning of ID proteins of the cardiac muscle can become the basis for the creation of new therapeutic approaches to the treatment and prevention of cardiac pathologies. SIRT1 may be an interesting cardioprotective variant due to its wide functional significance. SIRT1 activation triggers nuclear transcription programs that increase the efficiency of cellular, mitochondrial metabolism, increases resistance to oxidative stress, and promotes cell survival. It can be assumed that SIRT1 can not only provide a protective effect at the cardiomyocytes level, leading to an improvement in mitochondrial and metabolic functions, reducing the effects of oxidative stress and inflammatory processes, but also have a protective effect on the functioning of IDs structures of the cardiac muscle.

Growth hormone releasing peptide-6 (GHRP-6) prevents doxorubicin-induced myocardial and extra-myocardial damages by activating prosurvival mechanisms

“…Dox has been known since late 1960s, and its use in the oncological armamentarium remains as a first-line drug for the treatment of a wide variety of cancers of epithelial and non-epithelial origin. Nonetheless, its short and long-term cardiotoxic effects are of foremost clinical significance ( Podyacheva and Toropova, 2022 ). Myriad of molecules have been historically investigated with the expectation to neutralize specific or multiple targets within the pleomorphic cardiomyocyte damaging cascade ( Dulf et al, 2023 ).…”

Nrf2: a dark horse in doxorubicin-induced cardiotoxicity

“…The controversy regarding the p38 MAPK signaling pathway is also present in doxorubicin-induced cardiotoxicity. It has been discovered that doxorubicin can promote the activation of p38 MAPK and thus inducing the activation of inflammatory signals such as NF-κB to promote the expression of inflammatory factors such as interleukin-1β (IL-1β), IL-6, IL-17 and tumor necrosis factor alpha (TNF-α) to induce inflammation, while inhibiting this pathway has the opposite effect [ 122 , 124 ]. However, it has also been reported that doxorubicin induces cardiomyocyte apoptosis by inhibiting p38 MAPK and its downstream factor Nrf2.…”

Cumulative antitumor effect of bismuth lipophilic nanoparticles and cetylpyridinium chloride in inhibiting the growth of lung cancer

“…8 Surgery is the first treatment option for LC patients, followed by radiotherapy and chemotherapy. Drugs like doxorubicin and mitomycin are obsolete and no longer used 9–11 while crizotinib, erlotinib, and gefitinib are more commonly used today. 12–14 Research for new treatments continues in order to improve efficacy, reduce adverse side-effects, and lower cost.…”