Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems
02 Aug 2012-Journal of Pharmacy and Pharmacology (John Wiley & Sons, Ltd)-Vol. 65, Iss: 2, pp 157-170
TL;DR: The frontline drug doxorubicin has been used for treating cancer for over 30 years but causes toxicity to most major organs, especially life‐threatening cardiotoxicity, which forces the treatment to become dose‐limiting.
Abstract: Objectives The frontline drug doxorubicin has been used for treating cancer for over 30 years. While providing a cure in select cases, doxorubicin causes toxicity to most major organs, especially life-threatening cardiotoxicity, which forces the treatment to become dose-limiting.
Key findings Doxorubicin is known to bind to DNA-associated enzymes, intercalate with DNA base pairs, and target multiple molecular targets to produce a range of cytotoxic effects. For instance, it causes the activation of various molecular signals from AMPK (AMP-activated protein kinase inducing apoptosis) to influence the Bcl-2/Bax apoptosis pathway. By altering the Bcl-2/Bax ratio, downstream activation of different caspases can occur resulting in apoptosis. Doxorubicin also induces apoptosis and necrosis in healthy tissue causing toxicity in the brain, liver, kidney and heart. Over the years, many studies have been conducted to devise a drug delivery system that would eliminate these adverse affects including liposomes, hydrogel and nanoparticulate systems, and we highlight the pros and cons of these drug delivery systems.
Summary Overall the future for the continued use of doxorubicin clinically against cancer looks set to be prolonged, provided certain enhancements as listed above are made to its chemistry, delivery and toxicity. Increased efficacy depends on these three aims being met satisfactorily as discussed in turn in this review.
Citations
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TL;DR: The physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes, and sensors, and examples of mitochondrial targeting of bioactive compounds are described.
Abstract: Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the cell and mitochondrial membrane potentials, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this Review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes, and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.
892 citations
TL;DR: The origin of DNA nanotechnology is reviewed, followed by summarizing state-of-the-art strategies for the construction of DNAnanostructures and drug payloads delivered by DNA nanovehicles and challenges and opportunities for DNA nanostructure-based drug delivery.
Abstract: Over the past decade, we have seen rapid advances in applying nanotechnology in biomedical areas including bioimaging, biodetection, and drug delivery. As an emerging field, DNA nanotechnology offers simple yet powerful design techniques for self-assembly of nanostructures with unique advantages and high potential in enhancing drug targeting and reducing drug toxicity. Various sequence programming and optimization approaches have been developed to design DNA nanostructures with precisely engineered, controllable size, shape, surface chemistry, and function. Potent anticancer drug molecules, including Doxorubicin and CpG oligonucleotides, have been successfully loaded on DNA nanostructures to increase their cell uptake efficiency. These advances have implicated the bright future of DNA nanotechnology-enabled nanomedicine. In this review, we begin with the origin of DNA nanotechnology, followed by summarizing state-of-the-art strategies for the construction of DNA nanostructures and drug payloads delivered ...
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References
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TL;DR: Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line and counters the death repressor activity of B cl-2, suggesting a model in which the ratio of Bcl-2 to Bax determines survival or death following an apoptotic stimulus.
6,193 citations
"Doxorubicin: an update on anticance..." refers result in this paper
...Bcl-2 is known for its antiapoptotic properties, which are usually opposed by Bax, and this balance between the two is critical as to whether a cell enters apoptosis or survives.([41,42]) Some studies suggest that doxorubicin employs its effects by stimulating components within the Fas/Fas ligand apoptosis pathways, but other studies have produced contradictory results....
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TL;DR: Bcl-2 and related cytoplasmic proteins are key regulators of apoptosis, the cell suicide program critical for development, tissue homeostasis, and protection against pathogens.
Abstract: Bcl-2 and related cytoplasmic proteins are key regulators of apoptosis, the cell suicide program critical for development, tissue homeostasis, and protection against pathogens. Those most similar to Bcl-2 promote cell survival by inhibiting adapters needed for activation of the proteases (caspases) that dismantle the cell. More distant relatives instead promote apoptosis, apparently through mechanisms that include displacing the adapters from the pro-survival proteins. Thus, for many but not all apoptotic signals, the balance between these competing activities determines cell fate. Bcl-2 family members are essential for maintenance of major organ systems, and mutations affecting them are implicated in cancer.
5,380 citations
"Doxorubicin: an update on anticance..." refers result in this paper
...Some studies suggest that doxorubicin employs its effects by stimulating components within the Fas/Fas ligand apoptosis pathways, but other studies have produced contradictory results.([43,44]) Doxorubicin is shown to downregulate Bcl-2 mRNA levels, a mechanism that is thought to be p53independent....
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TL;DR: AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor, uncovering a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.
3,328 citations
TL;DR: An overview of issues confirms that anthracyclines remain “evergreen” drugs with broad clinical indications but have still an improvable therapeutic index.
Abstract: The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.
3,320 citations
"Doxorubicin: an update on anticance..." refers background in this paper
...Other doxorubicin actions include free radical generation which causes further DNA damage, inhibition of macromolecule production, DNA unwinding/separation and increase in alkylation.([18,19]) A recent study reported doxorubicin’s ability to intercalate with not only nuclear DNA, but also mitochondrial DNA....
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...Cervical cancer([13]) Endometrial cancer([14]) Pancreatic cancer([15]) Prostate cancer([7]) Head and neck cancer([16]) Adrenal cortex cancer([17]) Skin cancer and mucous membranes (usually in patients suffering from AIDS – Kaposi’s sarcoma)([7]) Bone cancer – osteosarcoma, Ewing’s sarcoma([18]) Womb and uterine cancers – gestational trophoblastic tumours([7]) Lung cancer([19]) Breast cancer([20]) Stomach cancer([21]) Soft tissue sarcoma([7]) Multiple myeloma([7]) Pancreatic cancer([22]) Thyroid cancer([23]) Oktay Tacar et al....
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...The cell will then experience energy failure that would be irreversible, resulting in cell death.([19]) PARP-1’s role Oktay Tacar et al....
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TL;DR: Delivery may be less efficient in cranial tumors than in subcutaneous tumors, delivery may be reduced during tumor regression induced by hormonal ablation, and permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter.
Abstract: Novel anti-neoplastic agents such as gene targeting vectors and encapsulated carriers are quite large (approximately 100–300 nm in diameter) An understanding of the functional size and physiological regulation of transvascular pathways is necessary to optimize delivery of these agents Here we analyze the functional limits of transvascular transport and its modulation by the microenvironment One human and five murine tumors including mammary and colorectal carcinomas, hepatoma, glioma, and sarcoma were implanted in the dorsal skin-fold chamber or cranial window, and the pore cutoff size, a functional measure of transvascular gap size, was determined The microenvironment was modulated: (i) spatially, by growing tumors in subcutaneous or cranial locations and (ii) temporally, by inducing vascular regression in hormone-dependent tumors Tumors grown subcutaneously exhibited a characteristic pore cutoff size ranging from 200 nm to 12 μm This pore cutoff size was reduced in tumors grown in the cranium or in regressing tumors after hormone withdrawal Vessels induced in basic fibroblast growth factor-containing gels had a pore cutoff size of 200 nm Albumin permeability was independent of pore cutoff size These results have three major implications for the delivery of therapeutic agents: (i) delivery may be less efficient in cranial tumors than in subcutaneous tumors, (ii) delivery may be reduced during tumor regression induced by hormonal ablation, and (iii) permeability to a molecule is independent of pore cutoff size as long as the diameter of the molecule is much less than the pore diameter
2,340 citations
"Doxorubicin: an update on anticance..." refers background in this paper
...The diameter of these liposomes must be small enough to allow extravasation of the drug into the gaps found in permeable tumour blood vessels to reach the affected tissue.([77,78])...
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