The anthracycline category Doxorubicin (Dox) is a chemotherapeutic agent useful in the treatment of various adult and paediatric cancer patients [[1], [2], [3]]. However, the use of the Dox in clinics is limited by the risk of developing severe cardiotoxicity. It has been observed many times that patients treated with Dox or its derivatives develop cardiac complications even after the termination of the treatment [2,3]. The possibility of developing cardiomyopathy primarily depends on the dosage and duration of treatment but may also occur at low doses due to individual susceptibility (age, gender, and chronic conditions) [2]. Dox cardiotoxicity can be acute, occurring within 2–3 days after administration, or chronic, where it may show after 30 days of the last dose and may occur even after 10–15 years after the administration [3]. The manifestations of acute dose toxicity include arrhythmia, hypotension, and acute heart failure, which account for 11% of all incidences and are reversible and manageable [3]. The chronic dose of Dox leads to dilated cardiomyopathy in a dose- and time-dependent manner with a documented prevalence of cardiac failure of up to 48% in patients. Data showed that poor prognosis of these patients leads to a mortality rate of 50% in one year [3].

It is well documented that the primary cause of Dox-induced cardiomyopathy is increased oxidative stress, as evidenced by increased reactive oxygen species (ROS) production, enhanced lipid peroxidation, and reduced antioxidant levels in both cellular and animal models [2,4]. Elevated ROS levels in response to Dox treatment may result from different mechanisms, such as disruptions of the mitochondrial electron transport chain either directly through its interaction with mitochondrial enzymes such as NADH to undergo redox cycling between quinone and semiquinone states [5,6] or indirectly via compromising the mitochondrial genome, mitochondrial membrane phospholipid cardiolipin and mitochondrial biogenesis [7,8]. Similarly, there are several other mechanisms through which Dox exposure causes heart failure such as calcium dysfunction, endothelin-1, and topoisomerase-II [9]. Increased ROS by Dox has been reported to cause cardiomyoblast death by activating intrinsic and extrinsic pathways [10]. Although previous studies have highlighted the alteration of oxidative stress and apoptosis signaling pathways after Dox exposure in cardiomyocytes, few studies have revealed the structural alteration of organelles and their effect on cardiotoxicity.

The endomyocardial biopsies performed in human hearts after Dox exposure reveal an increase in the sarcoplasmic reticulum and T-tubule size, accompanied by cytoplasmic vacuolization. There were nuclear changes such as chromatin clumping, nucleolar shrinkage, and the segregation of granular and fibrillar components [11]. Nuclear, mitochondrial, and cytoskeletal changes were also observed in cardiomyoblast after Dox exposure [12]. Despite a few observations on nuclear size after Dox exposure, no in-depth study was conducted to look for more details about nuclear membrane integrity, nuclear membrane proteins' involvement in nuclear morphological alteration, and cell survival.

Therefore, in the present study, we are interested to find the effect of Dox on nuclear size, nuclear membrane integrity, lamin A/C levels and its phosphorylation state. Lamin A/C is a structural filament proteins in the cell localized at the inner nuclear membrane in polymer form and encoded by the LMNA gene. Mutations in this gene produced a group of disorders called laminopathies. Many laminopathies cause a severe form of cardiomyopathy characterized by rapid progression, atrial arrhythmia, atrioventricular (AV) blocks, ventricular arrhythmia, and sudden cardiac death (SCD) [13]. Interestingly, this study found new insight regarding the effect of Dox on lamin A/C expression and its phosphorylation state, and their impact on nuclear membrane integrity and cell death.