Cytotoxicity of doxorubicin

Tab. 5.20 In vitro cytotoxicity of doxorubicin (DOX), idarubicin (IDA), and annanycin (ANN) with and without verapamil (VER) in sensitive HL-60S and resistant HL-60/DOX cells. (Reproduced from Tab. 3 of ref. 127 with permission from the American Society of Hematology)...

Bennis, S. Chapey, C. Couvreur, P. Robert, J. Enhanced cytotoxicity of doxorubicin encapsulated in polyiso-hexylcyanoacrylate nanospheres against multidrug-resistant tumour cells in culture. Eur. J. Cancer 1994, 1, 89-93. 

Figure 12.4. Effect of combined use of USMH (41°C) and PSC 833 on cytotoxicity of doxorubicin in the parent and MDR variant of MV522 and KB lines. Data were expressed as % inhibition calculated by the following formula % inhibition = [1 — (counts of viable drug-exposed cells/counts of viable non-drug-exposed cells)] x 100. All experiments were carried out in triplicate (mean standard deviation).

A., Eandi, M.R., Zara, M. and G.P. (2006) Intracellular accumulation and cytotoxicity of doxorubicin with different pharmaceutical formulations in human cancer cell lines. J. Nanosci. Nanotechnol,... 

Wong, H.L. A.M. Rauth R. Bendayan J.L. Manias M. Ramaswamy Z. Liu S.Z. Erhan X.Y. Wu. A new polymer-lipid hybrid nanoparticle system increases cytotoxicity of doxorubicin against multidrug-resistant human breast cancer cells. Pharm. Res. 2006, 23, 1574—1585. 

Figure 11 Cytotoxicity of doxorubicin (DOX) delivered as a free drug, in PA or PA/SDM nanoparticles against MCF-7 cells, as a function of drug concentration at (a) pH 7.4 and (b) 6.8. Data represent a meaniS.D., n = 7. (Adapted from Ref 92.)...

In mouse mammary tumor cells, treatment with black cohosh increased the cytotoxicity of doxorubicin and docetaxel and decreased the cytotoxicity of cisplatin, but did not alter the effects of radiation or 4-hydroperoxycyclophos-phamide (an analog of cyclophosphamide that is active in cell culture) (Rockwell et al. 2005). 

Xanthine dehydrogenase (EC 1.1.1.204), the enzymatic precursor of xanthine oxidase (EC 1.1.3.22) reacts with doxorubicin via a two-electron reduction (Yee and Pritsos 1997). This reduction is different from the modified and more extensively studied form xanthine oxidase, which reacts with doxorubicin via a one-electron reduction. Under hypoxic conditions, the formation of large quantities of 7-deoxydoxorubicin aglycone, a deactivation product of doxorubicin metabolism, may serve to moderate the antineoplastic activity of doxorubicin. Under aerobic conditions, however, xanthine dehydrogenase activation led to a greater rate of formation of oxygen radicals than xanthine oxidase thereby possibty potentiating the cytotoxicity of doxorubicin to aerobic tumour cells. 

The study of the cytotoxicity of doxorubicin, a red coloured molecule for which cytotoxic effects involve at least three mechanisms (necrosis/apoptosis, mitochondrial activity and oxidative stress) connected in some way or another, is a prime example to demonstrate the relevance of fluorimetric methods. 

Figure 6 (A) Cytotoxicity of SDS, Calcein-AM and Alamar blue assays (B) Cytotoxicity of DNP, Calcein-AM and Alamar blue assays (C) Cytotoxicity of doxorubicin, Calceln-AM assay (D) Cytotoxicity of doxorubicin, H2DCFDA assay.

Figure 2. Cytotoxicity of doxorubicin (1 and 2) and doxorubicin in the presence of 0.0 i% w/v Pluronic L61 (3 and 4) with respect to drug sensitive (i and 4) MCF-7 and drug resistant (2 and 3) MCF-7ADR cell subiines.

Table 2. Cytotoxicity of doxorubicin alone and of doxorubicin in the presence of 0.01 % w/v Plutonic L61 against a panel of multidrug resistant cell sublines and their sensitive parental lines...

Table 4. Cytotoxicity of doxorubicin against various drug resistant cell lines in the presence of...

Fig. 20.10. Enhancement of doxorubicin cytotoxicity in LoVo-resistant cells by verapamil and analogues. (Adapted from Ref. [77]). The results are expressed as fold increase in cytotoxicity represented by the ratio of doxorubicin IC50 in the absence and presence of verapamil and analogues (solid bars). The verapamil concentrations used were the minimal cytotoxic concentrations (IC20)-The compounds used were verapamil (1) ...

Horowitz AT, Barenholz Y, Gabizon AA. In vitro cytotoxicity of liposome-encapsulated doxorubicin dependence on liposome composition and drug release. Biochim Biophys Acta 1992 1109 203-209. 

Since the discovery of vesicular structures, termed liposomes, by Alec Bangham, a tremendous amount of work on applications of liposomes has emerged. The use of small unilamellar liposomes as carriers of drugs for therapeutic applications has become one of the major fields in liposome research. The majority of these applications are based on the encapsulation of water-soluble molecules within the trapped volume of the liposomes. Long circulating poly(ethylene glycol) (PEG) modified liposomes with cytotoxic drugs doxorubicin, paclitaxel, vincristine, and lurtotecan are examples of clinically applied chemotherapeutic liposome formulations (1,2). 

Miglietta A. et al., Cellular uptake and cytotoxicity of solid lipid nanospheres (SEN) incorporation doxorubicin or paclitaxel, Int. J. Pham., 210, 61, 2000. 

In addition to the intercalation mechanism described, the anthracycline ring of doxorubicin can undergo a one-electron reduction to form free radicals and participate in further electron transfer. These highly active substances can then react with tissue macromolecules. This type of interaction suggests an alternative mechanism of cytotoxicity for the anthracyclines. In particular, the cardiac toxicity of anthracyclines may result from the generation of free radicals of oxygen. 

Based on the same principle of modulation of drug absorption, other less known botanicals could produce similar or different effects compared to St. John s wort. Rosemary (Rosemarinus officinalis Labiatae) is a commonly used dietary botanical that has been found to have a chemopreventive effect (24). Furthermore, in drug-resistant MCF-7 human breast cancer cells expressing P-glycoprotein, methanol extracts of Rosemary at two concentrations (16.5 and 85 pg/mL) inhibited the efflux and increased intracellular accumulation of doxorubicin and vinblastine, two chemotherapeutic drugs that are known substrates of P-glycoprotein. Treatment of drug-resistant cells with the extracts also increased the cytotoxic effects of doxorubicin. On the other hand, in wild-type MCF-7 cells that do not express... 

I. Muller, A. Jenner, G. Bruchelt, D. Niethammer and B. Halliwell, Effect of concentration on the cytotoxic mechanism of doxorubicin—apoptosis and oxidative DNA damage, Biochem. Biophys. Res. Commun., 230 (1997) 254-257. 

In vitro studies with several tumor cell lines have shown vitamin C to enhance the cytotoxic activity of doxorubicin, cisplatin, paclitaxel, dacarbazine, 5-FU, and bleomycin. Vitamin C has also been shown to increase drug accumulation and to partially reverse vincristine resistance of human nonsmall-cell lung cancer cells. 

P-Carotene has been shown to enhance the cytotoxicity of melphalan and BCNU on human squamous carcinoma cells and of cisplatin and dacarbazine on melanoma cells. In mice with transplanted mammary carcinoma, P-carotene enhanced the antitumor effect of cyclophosphamide, and in mice transplanted with Fsall fibrosarcoma or SCC VII carcinoma, p-carotene enhanced the antitumor effect of melphalan, BCNU, doxorubicin, and etoposide. p-Carotene (5 to 50 mg/kg) has been shown to reduce the genotoxicity of cyclophosphamide in mice and of mitomycin C, methyl methanesulfonate, and bleomycin in cultured cells. P-Carotene also reduced the rate of tumor induction in animals receiving chronic low doses of cyclophosphamide. 

---