Apoptosis doxorubicin

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 spontaneously hypertensive rats, the nephropathy and the intestinal toxicity produced by 1 mg doxorubicin per kg x week were more severe than those resulting from 0.25 mg (therapeutically equivalent dose) or 0.5 mg mitoxantrone per x week (Herman et al. 1997). Apoptosis of cardiac myocytes was not induced by either drug, but involved cardiac dendritic cells in spontaneously hypertensive rats given doxorubicin. Apoptosis in renal tubular epithelium was comparable in spontaneously hypertensive rats given doxorubicin and the higher dose of mitoxantrone. Doxorubicin induced more frequent apoptosis in intestinal epithelium than did the higher dose of mitoxantrone. 

Green PS, Leeuwenburgh C (2002) Mitochondrial dysfunction is an early indicator of doxorubicin-induced apoptosis. Biochimica et Biophysica Acta-Molecular Basis of Disease 1588 94-101. 

Kluza J, Marchetti P, Gallego MA, Lancel S, Fournier C, Loyens A, Beauvillain JC, Bailly C (2004) Mitochondrial proliferation during apoptosis induced by anticancer agents effects of doxorubicin and mitoxantrone on cancer and cardiac cells. Oncogene 23 7018-7030. 

Transfection ofmouse SlPphosphatase into HEK 293 cells, resulting in a 3-fold increase in membrane SIP phosphatase activity, caused a 50% deaease in SIP levels (reduced by 0.6 pmol/nmol phospholipid) and a 2 fold inaease in ceramide (inaeased by 23 pmol/nmol phospholipid) whereas sphingosine levels were similar to vector controls (0.8 pnnol/nmol phosphohpid). SIP phosphatase transfected cells underwent apoptosis in response to serum withdrawal, C2-ceramide, peroxide or doxorubicin with 2-3 fold higher frequency compared to vector-transfected control cells. Surprisingly, exogenously added SIP, which normally confers protechon, inaeased apoptosis. This may be due to its metabolism to ceramide (Mandala et al, 2000) although other factors may also be involved. 

Lucci, A., Han, T. Y., Liu, Y. Y., Giuliano, A. R, and Cabot, M. C., 1999b, Multidrug resistance modulators and doxorubicin synergize to elevate ceramide levels and elicit apoptosis in drug-resistant cancer cells. Cancer 86 299-310. 

K4. Konopleva, M., Tari, A., Lopez-Berestein, A., and Andreeff, M., Inhibition of Bcl-2 with liposomal-derived antisense oligonucleotides (AS-ODN) induces apoptosis and increases the sensitivity of primary acute myeloid leukemia (AML) cells and cell lines to cytosine arabi-noside and doxorubicin. Blood 90 (suppl. 1), 10494a (1997). 

The dimers were studied more closely in HL-60 leukaemia and Jurkat cell lines, and it was found that they have activities comparable to the clinically nsed anticancer drng doxorubicin. In terms of general toxicity to normal cells, it was observed that dimers 115 and 116 were not toxic to lymphocytes at doses approaching 100 p,M. In preliminary studies, apoptotic cell death was observed on exposnre to these componnds and further studies are ongoing to elucidate the underlying mechanism of apoptosis. For purposes of comparison, the corresponding phosphate ester monomers 117 and 118 were prepared and proved to have no antitumour activity in the cell lines examined. This result is important, because it rules out any role of the phosphate ester functionality in mediating the observed cytotoxic effects and emphasizes the necessity for a bivalent unit. 

Investigators found that human breast cancer cell lines with BRCAl mutations showed a twofold to fourfold increase in apoptosis after treatment with ionizing radiation, cisplatin, or doxorubicin, compared with cells free of mutations. They also found that BRCAl tumor cell lines were resistant to other agents, such as paclitaxel (Taxol) and docetaxel (Taxotere), treatments used commonly in ovarian cancer and advanced-stage breast cancers. 

Mizutani H, Tada-Oikawa S, Hiraku Y, et al. Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide. Life Sci. 2005 76 1439-1453. 

Wang S, Konorev EA, Kotamraju S, et al. Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms, intermediacy of H(2) 0(2)- and p53-dependent pathways. J Biol Chem. 2004 279 25535-25543. 

Wu et al. (1998) noted that doxorubicin-induced apoptosis in lymphoid cells was blocked by pepstatin A, which is an inhibitor of cathepsin D. These investigators also observed that cathepsin D was induced through p53 DNA-binding sites at the cathepsin D promoter. Moreover, they have found that, compared to fibroblasts from wild-type mice, cathepsin D-/- fibroblasts from gene knock-out mice exhibited increased resistance to death caused by doxorubicin. Also, in serum-deprived rat PC 12 cells undergoing apoptosis, the amount of cathepsin B has been observed to decline, while the level of cathepsin D increased (Shibata et al, 1998), and, in our laboratory (Kagedal et al., 2001), the same phenomenon was recently seen in human fibroblasts exposed to naphthazarin. 

Cuvillier, O., Nava, V.E., Murthy, S.K., Edsall, L.C., Levade, T., Milstien, S. and Spiegel, S., 2001, Sphingosine generation, cytochrome c release, and activation ofcaspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells, Cell Death Differ 8 162-171. 

Black cohosh 2. Caffeine 3. Evening primrose oil 4. Scutellaria baicalensis 5. Starflower (borage) 1. Docetaxel 2. Paditaxel 3. Doxorubicin 4. Tamoxifen 5. Cisplatin 6. Vinorelbine t cytotoxic properties Unknown mechanism (black cohosh). Caffeine t cytotoxic effects of cisplatin wogonin present in Scutellaria enhances etoposide-induced apoptosis. Gamolenic acid found in evening primrose oil and borage potentiated the in vitro toxicity of paditaxel and vinorelbine, attributed to an unsaturated fatty acid as modulators of tumour cell chemosensitivity Be aware and avoid concomitant use... 

Neville-Webbe, H.L., Rostami-Hodjegan, A., Evans, C.A., Coleman, R.E., and Holen, I. (2005). Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells. Int J Cancer 113 364-371. 

Andrieu-Abadie N, Jaffrezou JP, Hatem S, Laurent G, Levade T, Mercadier JJ. L-Carnitine prevents doxorubicin-induced apoptosis of cardiac myocytes role of inhibition of ceramide generation. 125. FASEB J. 1999 13 1501-1510. 

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