Drug Combinations and Mechanisms: A Short Analysis

Sophia Lee^*
*Correspondence: Sophia Lee, Department of Medical Oncology, Zhejiang University, Hangzhou, P.R. China, Email:

Keywords

Cardiovascular disease • Radiation treatment • Antioxidants • Cardiomyocytes • Cardiovascular toxicity

Introduction

As cancer mortality declines and the population that is still alive ages, the proportion of cancer patients who also have heart disease rises. Cancer treatment is linked to an increased risk of cardiovascular disease in cancer survivors, who are more likely to develop it than to have a tumor recur. Heart failure and arrhythmia are two common cardiovascular side effects of anticancer drugs. Older breast cancer survivors have a higher risk of dying from heart disease than from the disease itself. Cardiotoxicity has also overtaken the tumor as the second leading cause of long-term mortality, according to a cohort study of pediatric cancer survivors. In 1976, the first report of cardiotoxicity in juvenile patients receiving DOX was made. Since then, additional initiatives have been launched to separate the cardiotoxic and anticancer effects of ANTs and further reduce toxicity. ANT's cardiotoxicity has also received more attention at the same time. The cumulative dose, administration schedule, and age all had an effect on the risk, according to studies.

As a result of a thorough understanding of the mechanism by which cancer develops, monoclonal antibodies, inhibitors, immunotherapy, and other medications have been developed. The cardio toxicity that these medications cause is a major factor in patient survival, prognosis, and quality of life, despite their effectiveness in treating cancer. As a result, the field of "cardiooncology" is now more advanced. Primary cardiomyopathy may be to blame for decreased heart function following cancer treatment because myocardial cells are directly damaged. Secondary cardiomyopathy is caused by changes in the innervation or the hormonal system. Instead, myocarditis is caused when inflammatory cells invade the myocardium. Evaluation and treatment of cardiotoxicity caused by anticancer medication or the malignant process it causes is the foundation of cardio-oncology. It is essential to strike a balance between antitumor efficacy and cardiac events associated with cancer therapy in order to pursue optimal cancer care, which includes extending meaningful lives and providing individuals with supportive cardiovascular care.

Researchers have focused on preventing and reducing cardiotoxicity associated with cancer treatment in order to accomplish this objective. Efforts to combine cardiovascular and anti-cancer medications while simultaneously achieving cardiac cleansing have contributed to the development of "tumour cardiology." Traditional cardio-oncology focuses primarily on cancer patients' cardiovascular disease risk. The likelihood that people with cardiovascular disease will develop cancer in the future is the foundation of reverse cardiooncology. The two disorders appear to interact in a complex way through these two developmental pathways. An understanding of this bidirectional interaction can be beneficial to the prevention and treatment of linked disorders, as well as the collaboration between cardiology and cancer. In this article, we look at how cancer treatment, combination therapy, and some recent developments in cardio-oncology reverse cardiotoxicity.

Literature Review

Advanced cancer is mostly treated with chemotherapy, radiation, targeted therapy, and immunotherapy; Every single one of them has been shown to be bad for the cardiovascular system. Chemotherapy and radiation therapyrelated cardiotoxicity is the leading cause of morbidity and mortality in cancer survivors [1]. The use of anti-nausea drugs during chemotherapy has been linked to known cardiotoxicity. On the other hand, relatively new medications like immunomodulation and target therapy have not been linked to many reports of cardiotoxicity. The method that ANTs use to fight cancer involves damaging DNA. They mostly affect cells that are growing in the S and G2 stages [2]. The parent nucleus of the anthracene ring forms a relatively stable complex by non-specific insertion parallel to the DNA base pair. The positive charge of the parent nucleus has a strong affinity for DNA because it has a negative charge. The quinone structure of the molecule makes it simple for it to participate in oxygen free radical-generating electron transfer processes. ANTs, on the one hand, are embedded in DNA and prevent DNA replication and transcription. However, the use of ANTs increases the production of reactive oxygen species, which in turn results in double-strand breaks in DNA and oxidative damage to nucleic acids [3].

ANTs also have a direct impact on topoisomerase type 2, DNA unwinding, helicase activity, and the subsequent strand separation of DNA. Acute and chronic cardiotoxicity can be distinguished by the time of onset. Myocardial damage, interstitial edoema, and inflammatory cell infiltration are examples of rare acute cardiotoxicity caused by ANT therapy [4]. The pathology of this condition is comparable to that of abrupt toxic myocarditis. Dilated cardiomyopathy, on the other hand, is a more common symptom of chronic cardiotoxicity caused by ANTs in both human hearts and laboratory models. The pathology is characterized by dilated heart chambers and an increased heart weight. Vacuolar degeneration and sarcoplasmic reticulum swelling and consolidation are the most common patterns in both human tissue and animal models [5].

Discussion

Chronic cardio toxicity is classified into early and late forms based on when it first manifests. Early-onset chronic cardio toxicity usually presents as a dilated and hypokinetic cardiomyopathy and results in HF. It usually arises within a year after therapy termination. After chemotherapy has ended, years or even decades, late-onset persistent cardio toxicity may appear. The latter produces H₂O₂, which has the ability to be changed into a number of ROSrelated compounds that ultimately result in DNA damage response and the death of many cardiomyocytes. According to numerous researches, the cardio toxicity of ANTs can be decreased by using antioxidants including N-acetyl cysteine, vitamin E, and coenzyme. However, persistent antioxidant use did not produce the anticipated outcome in several animal tests. As a result, it is unclear how much of an impact oxidative stress and the generation of primitive ROS have on the cardio toxicity caused by ANT. The fact that ANTs exhibit a specific preference for the mitochondria in cardiomyocytes is another intriguing element of ANT-induced cardiotoxicity. Studies have demonstrated a connection between mitochondrial malfunction and ROS generation. The abundant phospholipid cardiolipins on the inner mitochondrial membrane can directly bind to DOX, which can then block complexes I and II, obstruct the electron transport chain, and generate ROS. Then, ROS act on mitochondria, causing mitochondria to enlarge, causing the mitochondrial permeability transition pore to open, and causing the mitochondrial membrane potential to dissipate. In neonatal rat cardiomyocytes exposed to DOX, aberrant mitochondrial structure and mitochondrial damage have indeed been observed.

DOX hinders mitophagy by preventing Sestrin2 (SESN2) from interacting with Parkin and p62. Additionally, the DOX-induced regulation of mitochondrial autophagy may be linked to cytoplasmic p53, which binds to Parkin and prevents it from translocating to mitochondria to inhibit phagocytosis. Activation of the PINK1/Parkin pathway, which encourages PINK1/Parkin translocation to mitochondria, has been suggested by other studies to be the cause of cardiotoxicity and the signs of it. Reduced mitophagy also prevents cardiomyocyte cell death and reduces mitochondrial dysfunction. In addition to mitophagy, a process called "macroautophagic," in which DOX affects autophagy to cause cardiotoxicity, is investigated later. Autophagy's role in the cardiotoxicity caused by antitumor therapy has been questioned. Autophagy, a bulk breakdown pathway dependent on the lysosome, is necessary for maintaining cellular homeostasis. Autophagy begins with the activation of the adenosine 5'-monophosphate-activated protein kinase pathway and the inhibition of the mammalian target of rapamycin signaling pathway. However, autophagy inhibition-induced ANT-induced cardiotoxicity has been the focus of other studies. that DOX stimulates the phosphoinositide 3-kinase gamma/ protein kinase B downstream signaling pathway of Toll-like receptor 9, activating mTOR, which in turn suppresses Ulk-1 and prevents autophagy from beginning. discovered that the administration of DOX therapy did not sufficiently trigger autophagy in the heart.

It is challenging to pinpoint the specific involvement of autophagy in DOXinduced cardiotoxicity, and those investigations lacked a thorough evaluation of autophagic flux. Increased LC3-II levels might indicate a problem with autophagosome fusion or improved autophagosome formation. There are some distinctions between the clinical symptoms of acute cardiotoxicity and chronic cardiotoxicity brought on by DOX, and the cardiotoxicity of DOX is amount of the drug. Controversial findings could potentially be a result of research on dosage and modelling duration being lacking. However, regardless of whether DOX causes cardio toxicity by activating or suppressing autophagy, it is highly intriguing that reversing autophagy at that moment can reduce cell death.

Conclusion

This study discusses new developments in reverse cardio-oncology, the use of antineoplastic and cardio protective medications in combination, and the processes by which cancer therapy causes cardiovascular toxicity. Chemotherapy, radiotherapy, and surgery are the primary treatments for cancer. Radiotherapy can be used to treat cancers of the breast, thyroid, prostate, and head and neck. Ionizing molecules in radioactively damaged tissue, preventing DNA replication, and eliminating tumor cells are the primary ways that radiotherapy damages DNA.

Conflicts of Interest

None.

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