Cardiomyocyte apoptosis vs autophagy with prolonged doxorubicin treatment: comparison with osteosarcoma cells.

OBJECTIVE: Doxorubicin (Dox) is a frontline chemotherapeutic against osteosarcoma (OS) that is plagued by side effects, particularly in the heart. The specific objective of this article is to investigate whether low-dose Dox treatment had pro-autophagic effects in cardiomyocytes as well as osteosarcoma cells. METHODS: This study characterises apoptotic (Bax) and autophagic (Beclin-1) biomarker levels in human OS and cardiomyocyte cell lines as well as in various tissues when mice are exposed to low (1 mg/kg, thrice weekly) and high (3 mg/kg thrice weekly) dose Dox for a month. KEY FINDINGS: There was a decrease in Bax and increase in Beclin-1 in cardiac tissue in the high-dose group. Dox decreased Beclin-1 in the skin and liver, with no clear indication in the stomach, small intestine and testis. At low Dox doses of 10 and 100 nm in cardiomyocytes and OS cells, there is a pro-apoptotic effect, with a quicker response in the 100-nm condition, and a slower but steady increase of a pro-apoptotic response at the lower 10-nm dose. However, electron microscopy images revealed changes to human OS cells that resembled autophagy. Human prostate, breast and colorectal cells treated with 10-nm Dox showed ∼ 40% reduction in cell viability after 24 h. CONCLUSION: In culture, cells of both cardiomyocytes and OS revealed a predominant pro-apoptotic response at the expense of autophagy, although both seemed to be occurring in vivo.

Doxorubicin-induced death in tumour cells and cardiomyocytes: is autophagy the key to improving future clinical outcomes?

OBJECTIVES: Doxorubicin, a commonly used frontline chemotherapeutic agent for cancer, is not without side-effects. The original thinking that the drug causes necrosis in tumours has largely given way to its link with apoptosis over the past two decades. KEY FINDINGS: More recently, major biomarkers such as AMPK, p53 and Bcl-2 have been identified as important to apoptosis induction by doxorubicin. It is Bcl-2 and its interaction with Beclin-1 that has refocussed research attention on doxorubicin, albeit this time for its ability to induce autophagy. Autophagy can be either anticancerous or procancerous however, so it is critical that the reasons for which cancer cells undergo this type of cell biological event be clearly identified for future exploitation. SUMMARY: Taking a step back from treating patients with large doses of doxorubicin, which causes toxicity to the heart amongst other organs, and further research with this drug's molecular signalling in not only neoplastic but normal cells, may indeed redefine the way doxorubicin is used clinically and potentially lead to better neoplastic disease management.

Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems.

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.