Protective effect of Epothilone D against traumatic optic nerve injury in rats / 南方医科大学学报

OBJECTIVE@#To investigate the therapeutic effect of Epothilone D on traumatic optic neuropathy (TON) in rats.@*METHODS@#Forty-two SD rats were randomized to receive intraperitoneal injection of 1.0 mg/kg Epothilone D or DMSO (control) every 3 days until day 28, and rat models of TON were established on the second day after the first administration. On days 3, 7, and 28, examination of flash visual evoked potentials (FVEP), immunofluorescence staining and Western blotting were performed to examine the visual pathway features, number of retinal ganglion cells (RGCs), GAP43 expression level in damaged axons, and changes of Tau and pTau-396/404 in the retina and optic nerve.@*RESULTS@#In Epothilone D treatment group, RGC loss rate was significantly decreased by 19.12% (P=0.032) on day 3 and by 22.67% (P=0.042) on day 28 as compared with the rats in the control group, but FVEP examination failed to show physiological improvement in the visual pathway on day 28 in terms of the relative latency of N2 wave (P=0.236) and relative amplitude attenuation of P2-N2 wave (P=0.441). The total Tau content in the retina of the treatment group was significantly increased compared with that in the control group on day 3 (P < 0.001), showing a consistent change with ptau-396/404 level. In the optic nerve axons, the total Tau level in the treatment group was significantly lower than that in the control group on day 7 (P=0.002), but the changes of the total Tau and pTau-396/404 level did not show an obvious correlation. Epothilone D induced persistent expression of GAP43 in the damaged axons, detectable even on day 28 of the experiment.@*CONCLUSION@#Epothilone D treatment can protect against TON in rats by promoting the survival of injured RGCs, enhancing Tau content in the surviving RGCs, reducing Tau accumulation in injured axons, and stimulating sustained regeneration of axons.

Multiple Effects of a Novel Epothilone Analog on Cellular Processes and Signaling Pathways Regulated by Rac1 GTPase in the Human Breast Cancer Cells

The epothilones are a class of microtubule inhibitors that exhibit a strong antitumor activity. UTD2 is a novel epothilone analog generated by genetic manipulation of the polyketide biosynthetic gene cluster. This study investigated the effects of UTD2 on the actin cytoskeleton and its critical regulators, and the signaling pathways which are essential for cell motility, growth and survival in MCF-7 breast cancer cells. Results showed that UTD2 inhibited the cellular functions of actin cytoskeleton, such as wound-closure, migration and invasion, as well as adhesion. Our study further demonstrated that UTD2 suppressed Rac1 GTPase activation and reduced the activity of PAK1, which is a downstream effector of Rac1, while the activity of Cdc42 was not affected. Additionally, the phosphorylation of p38 and ERK were significantly inhibited, but the phosphorylation of JNK remained the same after UTD2 treatment. Moreover, UTD2 inhibited the activity and mRNA expression of MMP-2, which plays a key role in cell motility. UTD2 also reduced the phosphorylation of Akt, which is an important signaling kinase regulating the cell survival through Rac1. Furthermore, UTD2 interrupted the synergy between Rac1 and Raf in focus formation assays. Taken together, these results indicated that UTD2 exerted multiple effects on the actin cytoskeleton and signaling pathways associated with Rac1. This study provided novel insights into the molecular mechanism of the antineoplastic and antimetastatic activities of epothilones. Our findings also suggest that the signaling pathways regulated by Rac1 may be evaluated as biomarkers for the response to therapy in clinical trials of epothilones.

A Case Report of Breast Cancer with Extensive Pulmonary Lymphovascular Tumor Emboli / 한국유방암학회지

We describe a patient with breast cancer who relapsed with an extensive pulmonary lymphovascular tumor embolism. A 38-year-old female, who previously received neoadjuvant chemotherapy and curative resection of breast cancer, underwent adjuvant chemotherapy and was referred to the emergency room because of sudden-onset pleuritic chest pain lasting for 10 days. Despite a trial of empirical antibiotics, the chest pain and the extent of consolidative lung lesion on chest radiographs rapidly aggravated. We performed an open lung biopsy to confirm the etiology. The histopathological review revealed a hemorrhagic infarction caused by lymphovascular tumor emboli from a metastatic breast carcinoma. Palliative first-line chemotherapy was administered, consisting of ixabepilone and capecitabine, and the lung lesion improved markedly.

[Treatment of hormone-resistant prostate cancer]

Two recent randomized Phase-three studies [TAX 327 and SWOG 9916] have demonstrated that Docetaxel improved the survival rate of patients with hormone-resistant prostate cancer. Other drugs such as Mitoxantrone, vinorelbine, saraplatin and Epothilone are recommended as second-line treatment where Docetaxel treatment has failed. Treatment with Atrasentan, an endothelin-receptor antagonist, or other inhibitors of angiogenesis combined with Docetaxel is presently under evaluation. Zoledronic acid, alone or in association with chemotherapy, and the use of radioisotopes [strontium-89, samarium 153 and radium 223] are palliative treatment options for multiple painful bone metastases in hormone-resistant cancer. Collectively, these treatment options reduce the risk of mortality, prevent the complications associated with disease progression and improve the patients' quality of life. Better understanding of the alternative pathways for androgen receptor signaling, the role of estrogen receptors, cytokines and stromal growth factors contributing to hormone resistance may lead to new treatment strategies

The PKS/NRPS hetero-gene cluster of epothilones / 生物工程学报

Novel macrolides epothilones, produced by cellulolytic myxobacterium Sorangium cellulosum, have the activity to promote microtubule assembly, and are considered to be a potential successor to the famous antitumor drug taxol. The biosynthetic genes leading to the epothilones are clustered into a large operon. The multi-enzyme complex is a hetero-gene cluster of polyketide synthase (PKS) and non-ribosomal peptide synthetases (NRPS) and contains several functional modules, i.e. a loading module, one NRPS module, eight PKS modules, and a P450 epoxidase. The former ten modules biosynthesize desoxyepothilone (epothilones C and D), which is then epoxidized at C12 and C13 and converted into epothilones (epothilones A and B) by the P450 epoxidase. The NRPS module is responsible for the formation of the thiazole side chain from cysteine. The biosynthesis procedure of epothilones can be divided into 5 stages, i.e. formation of holo-ACP/PCP, chain initiation and thiazole ring formation, chain elongation, termination and epoxidation, and post-modification. The analysis of the gene cluster and the biosynthetic pathway reveals that novel epothilone analogs could not only be produced by chemical synthesis/modification, tranditional microbial technologies, but also can be genetically manipulated through combinatiorial biosynthesis approaches.