The anthracycline antibiotics: antitumor drugs that alter chromatin structure

Rabbani, Azra; Finn, Ron M.; Ausió, Juan

doi:10.1002/bies.20160

Cited by 131 publications

(118 citation statements)

References 60 publications

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“…The aromatic rings are crucial to the bioactivities of many aromatic polyketides (16). For example, the conjugated aromatic ring system in the anthracycline polyketides (such as doxorubicin) is essential in intercalating at the CpG steps of the DNA helix, resulting in the inhibition of DNA replication and transcription.…”

Section: Strongly Diminished Rm80 Production (Ratio Of [4 ϩ 5]/[6] ͻmentioning

confidence: 99%

Crystal structure and functional analysis of tetracenomycin ARO/CYC: Implications for cyclization specificity of aromatic polyketides

Ames

Korman

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

154

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Polyketides are a class of natural products with highly diverse chemical structures and pharmaceutical activities. Polyketide cyclization, promoted by the aromatase/cyclase (ARO/CYC), helps diversify aromatic polyketides. How the ARO/CYC promotes highly specific cyclization is not well understood because of the lack of a first-ring ARO/CYC structure. The 1.9 Å crystal structure of Tcm ARO/CYC reveals that the enzyme belongs to the Bet v1-like superfamily (or STAR domain family) with a helix–grip fold, and contains a highly conserved interior pocket. Docking, mutagenesis, and an in vivo assay show that the size, shape, and composition of the pocket are important to orient and specifically fold the polyketide chain for C9-C14 first-ring and C7-C16 second-ring cyclizations. Two pocket residues, R69 and Y35, were found to be essential for promoting first- and second-ring cyclization specificity. Different pocket residue mutations affected the polyketide product distribution. A mechanism is proposed based on the structure-mutation-docking results. These results strongly suggest that the regiospecific cyclizations of the first two rings and subsequent aromatizations take place in the interior pocket. The chemical insights gleaned from this work pave the foundation toward defining the molecular rules for the ARO/CYC cyclization specificity, whose rational control will be important for future endeavors in the engineered biosynthesis of novel anticancer and antibiotic aromatic polyketides.

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Section: Strongly Diminished Rm80 Production (Ratio Of [4 ϩ 5]/[6] ͻmentioning

confidence: 99%

Crystal structure and functional analysis of tetracenomycin ARO/CYC: Implications for cyclization specificity of aromatic polyketides

Ames

Korman

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

154

View full text Add to dashboard Cite

show abstract

“…Upon entering the nucleus, doxorubicin inhibits topoisomerase II and helicase activities, and interferes with DNA double helix religation. This stops DNA replication and induces apoptosis (Rabbani et al 2005). Apoptosis may occur via activation of pro-apoptotic proteins, since antisense against Bcl-2 and Bcl-xL sensitizes breast cancer cells to this drug (Simoes-Wust et al 2002).…”

Section: Properties Of Selected Chemotherapeutic Drugsmentioning

confidence: 99%

Novel roles of prolactin and estrogens in breast cancer: resistance to chemotherapy

LaPensee

Ben‐Jonathan

2010

Endocrine-Related Cancer

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Resistance to chemotherapy is a major complication in the treatment of advanced breast cancer. Estrogens and prolactin (PRL) are implicated in the pathogenesis of breast cancer but their roles in chemoresistance have been overlooked. A common feature to the two hormones is activation of their receptors by diverse compounds, which mimic or antagonize their actions. The PRL receptor is activated by lactogens (PRL, GH, or placental lactogen) originating from the pituitary, breast, adipose tissue, or the placenta. Estrogen receptors exist in multiple membrane-associated and cytoplasmic forms that can be activated by endogenous estrogens, man-made chemicals, and phytoestrogens. Here, we review evidence that low doses of PRL, estradiol (E 2 ), and bisphenol A (BPA) antagonize multiple anticancer drugs that induce cell death by different mechanisms. Focusing on cisplatin, a DNA-damaging drug which is effective in the treatment of many cancer types but not breast cancer, we compare the abilities of PRL, E 2 , and BPA to antagonize its cytotoxicity. Whereas PRL acts by activating the glutathione-S-transferase detoxification enzyme, E 2 and BPA act by inducing the antiapoptotic protein Bcl-2. The implications of these findings to patients undergoing chemotherapy are discussed.

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“…There are several mechanisms by which their actions affect tumor cells, such as inhibition of mammalian DNA topoisomerase II, generation of free radicals leading to DNA damage and lipid peroxidation and DNA cross linking (35)(36)(37). However, its clinical use is hampered by serious problems such as development of resistance in tumor cells and side effects, most notably in the form of chronic cardiomyopathy and congestive heart failure.…”

Section: Discussionmentioning

confidence: 99%

Induction of apoptosis by the angucyclinone antibiotic chemomicin in human tumor cells

He¹

2009

Oncol Rep

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Abstract. Chemomicin (CHM), an angucyclinone antibiotic extracted from the fermentation broth of Nocardia Mediterranei subsp. Kanglensis 1747-64, shows immunosuppressive activity. However, whether it can inhibit growth of tumor cells remains elusive. In the present study, we show that CHM potently inhibited the proliferations of eight various types of human tumor cell lines and non-cross resistant to multidrugresistant cells. In contrast to action of doxorubicin, the generation of reactive oxygen species was observed as early as 30 min after addition of CHM and its process did not involve iron. The apoptotic cells with chromatin condensation and Annexin V staining markedly increased after the human hepatoma HepG2 was exposed to 1, or 2 μg/ml CHM for 24 h. In the CHM-induced apoptosis, robust increment of p53 expression, activation of caspase-3, -7, -8, -9, cleavage of PARP and the phosphorylation of p38 and JNK, were detected by Western blot analysis. Further investigation revealed the disruption of mitochondrial membrane potential in the cells with CHM incubation for 4 h. Taken together, the results demonstrated that potent proliferation inhibitory effect of CHM on tumor cells is due to activation of the apoptotic pathway.

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The anthracycline antibiotics: antitumor drugs that alter chromatin structure

Cited by 131 publications

References 60 publications

Crystal structure and functional analysis of tetracenomycin ARO/CYC: Implications for cyclization specificity of aromatic polyketides

Crystal structure and functional analysis of tetracenomycin ARO/CYC: Implications for cyclization specificity of aromatic polyketides

Novel roles of prolactin and estrogens in breast cancer: resistance to chemotherapy

Induction of apoptosis by the angucyclinone antibiotic chemomicin in human tumor cells

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