Imatinib Reverses Doxorubicin Resistance by Affecting Activation of STAT3-Dependent NF-κB and HSP27/p38/AKT Pathways and by Inhibiting ABCB1

Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted) or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec), reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-κB/p65 nuclear localization and repression of NF-κB targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-κB, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-κB inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline-induced apoptosis.     

Allozyme diversity in endemic flowering plant species of the Juan Fernandez Archipelago, Chile: ecological and historical factors with implications for conservation

The level and apportionment of allozyme diversity were determined for 29 endemic (and 1 native) species from the Juan Fernández Islands, Chile. Mean diversities at the species level (H(es) = 0.065) are low but comparable to those measured for other insular endemics in the Pacific. A high mean proportion (0.338) of species-level diversity resides among populations. Diversity statistics were compared for species in different ecological-life history trait categories and abundance classes. Species occurring in large populations and those present in scattered small populations have higher diversities than species occurring in one or two populations. Although not significant with the conservative statistical test employed, lower diversity was found in highly selfing species as compared to animal- or wind-pollinated species. The apportionment of genetic diversity within and among populations (G(ST) values) is not significantly different for any of the species categories. Of particular interest is the lack of difference between animal- and wind-pollinated species because previous analyses of large data sets showed higher differentiation between populations of animal- than wind-pollinated species. Historical factors, both ecological and phylogenetic in nature, can influence the level and apportionment of diversity within insular endemics, and thus ecological correlates of diversity seen in many continental species may not apply to endemics. The results have several conservation implications. The preservation of large populations or several small populations is important for conserving diversity within species because when species are reduced to one or two populations, allozyme diversity is sharply reduced. High mean G(ST) values for the species examined illustrate the need for conserving as many populations as possible, either in the wild or in the garden, to preserve maximal diversity within species. Effective conservation strategies require empirical knowledge of each species.