Doxorubicin (Dox) is an anthracycline cell growth inhibitor. It interacts with DNA by inserting and inhibiting macromolecule biosynthesis, preventing the recombination of the DNA double helix, thereby effectively inhibiting tumor growth. Currently, doxorubicin is widely used to treat hematological malignancies and solid tumors, including antibody-drug conjugates (ADCs).

What is Doxorubicin?

Doxorubicin, which has the chemical formula C27H29NO11, is a potent antibiotic. It is a member of the anthracycline medication class, which is well-known for its capacity to obstruct the body's natural propensity for cancer cells to proliferate and spread. Doxorubicin's efficacy in treating a range of diseases, such as breast cancer, leukemia, lymphoma, and sarcoma, has been extensively researched in medication development. It is a potent weapon in the fight against illness because of its capacity to specifically target and eradicate cancer cells. To further strengthen its anti-cancer effects, doxorubicin can also be used effectively in conjunction with other chemotherapy medications. Apart from its direct anticancer actions, doxorubicin's potential in drug delivery systems has been investigated. Doxorubicin can now be delivered to tumor areas more effectively and with less toxicity to healthy tissue thanks to research into how to incorporate it into liposomes and nanoparticles. With less negative effects, chemotherapy may be administered more effectively thanks to this focused medication delivery approach.

Doxorubicin Structure

Doxorubicin is a complicated molecule with numerous constituent parts in terms of structure. Doxorubicin's primary structural component is a core anthraquinone ring that has been joined to a danoamine sugar molecule. The medication can enter cancer cells' DNA thanks to this anthraquinone ring, harming the cells' genetic material and stopping them from proliferating. Two additional elements connected to the anthraquinone ring are essential to the medication's action. The first is the glycosidic sugar moiety, which has a glycosidic link connecting it to the anthraquinone ring. Because it facilitates the drug's recognition and uptake by the cells, this sugar moiety is essential to the medication's ability to reach cancer cells. The hydroxyl group, which forms a hydroxyl bond with the anthraquinone ring, is the second connecting element. The drug's capacity to produce reactive oxygen species inside cancer cells is due to this hydroxyl group. Reactive oxygen species have the ability to harm cancer cells' DNA and cell membranes, which will ultimately result in the death of the cancer cells. Apart from these components, lipophilic side chains are also affixed to the anthraquinone ring in doxorubicin. The drug's capacity to pass across cell membranes and into cancer cells is due to this side chain. When the drug enters the cell, lipophilic side chains aid in keeping it there and boosting its cytotoxic effects.

Fig. 1. Nanomedicine based on doxorubicin prodrug (Eur J Med Chem. 2023, 258: 115612).

Doxorubicin Class

BOC Sciences is a leading supplier of ADCs cytotoxin, offering a wide range of high-quality cytotoxic products for research and development purposes. Our doxorubicin compounds are carefully synthesized and tested to ensure purity and quality. We can supply doxorubicin compounds in various quantities, from small-scale research samples to bulk orders for large-scale production. BOC Sciences also offers custom synthesis services for customers seeking specific derivatives that are not readily available on the market.

Doxorubicin Mechanism of Action

Doxorubicin is a broad-spectrum anthracycline anti-tumor antibiotic that can embed into DNA double strands, inhibit enzymes that regulate DNA superhelical structure, cause DNA damage and breakage, and exert anti-cancer effects. It can also exert anti-cancer effects through mechanisms such as inducing free radical production or metal complexation. Doxorubicin has a strong cytotoxic effect and has therapeutic effects on a variety of malignant tumors, including breast cancer, lung cancer, digestive system cancer, ovarian cancer, bladder cancer, sarcoma, lymphoma and acute leukemia. The mechanism of action of doxorubicin can be summarized as:

• Anthracyclines isolated from Streptomyces sp.
• Insertion into DNA results in inhibition of DNA synthesis and function.
• Inhibits transcription by inhibiting DNA-dependent RNA polymerase.
• Inhibition of topoisomerase II occurs by forming a cleavable complex with DNA and topoisomerase II, resulting in uncompensated DNA helix torsional tension, ultimately leading to DNA breakage.
• The formation of cytotoxic oxygen radicals leads to single- and double-stranded DNA breaks and subsequent inhibition of DNA synthesis and function.

Doxorubicin Cardiotoxicity

Accumulation of doxorubicin in the body may cause heart damage, leading to left ventricular dysfunction and heart failure. At present, the mechanism of doxorubicin-induced cardiotoxicity has not been clearly understood, and a comprehensive evaluation is needed to explore the direct relationship between various factors. The main underlying mechanism involves the generation of reactive oxygen species (ROS), which may lead to apoptosis or necrosis of cardiomyocytes.

Fig. 2. Combination anticancer therapy based on doxorubicin (Transl Oncol. 2024, 45: 101946).

• Oxidative Stress Damage

Oxidative stress injury is one of the most common mechanisms explaining the complex pathophysiology of doxorubicin-induced cardiotoxicity. Lipid peroxidation myocardial damage is caused by increased ROS production. ROS can induce different forms of cardiomyocyte death (apoptosis or necrosis), including the formation of superoxide (O2−), singlet oxygen (O2), etc., which can lead to cardiomyocyte damage.

• Apoptosis

As a part of the natural growth and development of the body, apoptosis occurs in multicellular organisms and is a physiological way of cell death. Doxorubicin can cause apoptosis through different mechanisms and has been extensively studied in acute and chronic cardiotoxicity. As mentioned above, one of the pathways involves the generation and oxidation mechanism of ROS, which is related to the apoptotic pathway. Increased oxidative stress has been shown to contribute to apoptosis, and antioxidants have been shown to inhibit this process.

• Mitochondrial Damage

Mitochondria are round or oval double-membrane bound organelles with a size of 0.5 ~ 10 um. The main function is to generate a large amount of energy in the form of ATP for use by cells. It is an important source of chemical energy. The long-lasting changes in mitochondrial energy metabolism and gene expression induced by doxorubicin may be related to epigenetic changes. It has been shown that doxorubicin treatment of cardiomyocytes results in decreased expression of genes encoding fatty acid beta-oxidation as well as expression of mitochondrial ATP-generating enzymes.

• Other Factors

Disturbances in cardiac muscle structure may play a role in doxorubicin cardiotoxicity. Actin is a giant protein that is a key component of the cardiac sarcomere, which extends from the M line to the Z line. This protein has multiple functions, and loss of actin integrity or function is directly related to the development of dilated cardiomyopathy. Cardiotoxicity caused by doxorubicin is accompanied by the disorder and loss of sarcomeric myofilaments. Doxorubicin induces rapid degradation of actin by activating the proteolytic pathway, leading to myocardial energy imbalance.

What is Doxorubicin Used For?

Doxorubicin is a powerful anthracycline chemotherapy drug widely used to treat many types of cancer, including leukemia, breast cancer, bladder cancer, and sarcomas. The drug works by interfering with the DNA of cancer cells, preventing them from multiplying and spreading. In addition to its use in traditional chemotherapy regimens, doxorubicin is also being investigated for its potential as an ingredient in targeted therapies, such as ADCs and liposomal formulations.

• Doxorubicin ADC Therapy

One of the most well-known applications of doxorubicin in drug development is in the creation of ADCs. ADCs are targeted therapies that combine the specificity of monoclonal antibodies with the potency of chemotherapy drugs. In ADCs, antibody components target specific antigens on the surface of cancer cells, delivering attached chemotherapy drugs directly to the tumor cells. This targeted approach helps minimize the side effects of chemotherapy by reducing the exposure of healthy tissue to the drug. Doxorubicin has been successfully incorporated into several ADCs currently in clinical development.

• Doxorubicin Liposomal

In addition to ADCs, doxorubicin has also been formulated in liposomal nanoparticles to improve its pharmacokinetic properties. Liposomal formulations of doxorubicin encapsulate the drug in a lipid bilayer, which can prolong blood circulation and enhance accumulation in tumor tissues due to the enhanced permeability and retention (EPR) effect. This targeted delivery system helps increase the therapeutic index of doxorubicin by reducing its contact with healthy tissue and minimizing its toxic side effects. An example of a liposomal formulation of doxorubicin is Doxil (PEGylated liposomal doxorubicin), which is approved for the treatment of ovarian cancer, AIDS-related Kaposi's sarcoma, and multiple myeloma. Doxil has been shown to have a lower incidence of cardiotoxicity than traditional doxorubicin, making it a first choice for patients at risk of heart damage.

• Doxorubicin Chemotherapy

Doxorubicin is also often used in combination with other chemotherapy drugs to treat various cancers. The drug is often included in standard chemotherapy regimens for cancers such as breast cancer, sarcoma and lymphoma. These combination therapies help increase the effectiveness of doxorubicin by targeting different pathways in cancer cells and reducing the potential for drug resistance. Although doxorubicin is a highly effective chemotherapy drug, it is associated with several serious side effects, most notably cardiotoxicity. This drug can cause damage to the heart muscle, leading to congestive heart failure or other heart complications. To reduce this risk, patients receiving doxorubicin need to be closely monitored for signs of cardiotoxicity, and the dose may need to be adjusted to reduce the risk of cardiac damage.