N-alkylisatin-based microtubule destabilizers bind to the colchicine site on tubulin and retain efficacy in drug resistant acute lymphoblastic leukemia cell lines with less in vitro neurotoxicity.

BACKGROUND: Drug resistance and chemotherapy-induced peripheral neuropathy continue to be significant problems in the successful treatment of acute lymphoblastic leukemia (ALL). 5,7-Dibromo-N-alkylisatins, a class of potent microtubule destabilizers, are a promising alternative to traditionally used antimitotics with previous demonstrated efficacy against solid tumours in vivo and ability to overcome P-glycoprotein (P-gp) mediated drug resistance in lymphoma and sarcoma cell lines in vitro. In this study, three di-brominated N-alkylisatins were assessed for their ability to retain potency in vincristine (VCR) and 2-methoxyestradiol (2ME2) resistant ALL cell lines. For the first time, in vitro neurotoxicity was also investigated in order to establish their suitability as candidate drugs for future use in ALL treatment. METHODS: Vincristine resistant (CEM-VCR R) and 2-methoxyestradiol resistant (CEM/2ME2-28.8R) ALL cell lines were used to investigate the ability of N-alkylisatins to overcome chemoresistance. Interaction of N-alkylisatins with tubulin at the the colchicine-binding site was studied by competitive assay using the fluorescent colchicine analogue MTC. Human neuroblastoma SH-SY5Y cells differentiated into a morphological and functional dopaminergic-like neurotransmitter phenotype were used for neurotoxicity and neurofunctional assays. Two-way ANOVA followed by a Tukey's post hoc test or a two-tailed paired t test was used to determine statistical significance. RESULTS: CEM-VCR R and CEM/2ME2-28.8R cells displayed resistance indices of > 100 to VCR and 2-ME2, respectively. CEM-VCR R cells additionally displayed a multi-drug resistant phenotype with significant cross resistance to vinblastine, 2ME2, colchicine and paclitaxel consistent with P-gp overexpression. Despite differences in resistance mechanisms observed between the two cell lines, the N-alkylisatins displayed bioequivalent dose-dependent cytotoxicity to that of the parental control cell line. The N-alkylisatins proved to be significantly less neurotoxic towards differentiated SH-SY5Y cells than VCR and vinblastine, evidenced by increased neurite length and number of neurite branch points. Neuronal cells treated with 5,7-dibromo-N-(p-hydroxymethylbenzyl)isatin showed significantly higher voltage-gated sodium channel function than those treated with Vinca alkaloids, strongly supportive of continued action potential firing. CONCLUSIONS: The N-alkylisatins are able to retain cytotoxicity towards ALL cell lines with functionally distinct drug resistance mechanisms and show potential for reduced neurotoxicity. As such they pose as promising candidates for future implementation into anticancer regimes for ALL. Further in vivo studies are therefore warranted.

Localized delivery of immunotherapy via implantable scaffolds for breast cancer treatment.

Breast cancer remains a leading global cause of morbidity and mortality. While the field of immunotherapy is a promising avenue of investigation and has revolutionized the standard of care for melanoma and lung cancer, modest response rates and a high incidence of immune-related adverse events often necessitate the administration of a sub-therapeutic dose or treatment cessation. Injectable and implantable drug delivery devices present a novel strategy to achieve sustained delivery of potent concentrations of drug directly to the tumor site and minimize systemic toxicity. This review will address the current limitations with conventional immunotherapy for breast cancer treatment, and the recent developments and future prospects in localized delivery strategies. We describe implantable scaffolds and injectable biomaterials for the localized delivery of immunotherapy, which can improve the safety and efficacy of immunotherapies. We discuss the limitations of these delivery systems, such as the influence of shape and material type on drug release and tumor uptake. The challenges of clinical translation, such as the availability of appropriate preclinical animal models and accurate reporting are also discussed. Considerations of these issues will pave the way for effective new therapies that will improve treatment response, patient survival and quality of life for breast cancer patients.

Depression and African Americans in the First Decade of Midlife: The Consequences of Social Roles and Gender.

OBJECTIVE: This study examined gender differences in how three social roles - marriage, parenthood, and employment - impact depressive symptoms and clinically significant depression for African Americans in the first decade of midlife, from 40 to 50 years old. Specifically, we sought to understand the associations between roles configurations (e.g., married parent versus employed only) and depressed mood as well as diagnosable depression. METHOD: The data for this study were extracted from the National Longitudinal Survey of Youth 1979 cohort (NLSY79). Constituting a representative sample of non-institutionalized Americans, NLSY respondents were interviewed each year from 1979 to 1994 and biennially thereafter. Our study included 2372 African Americans. We used ordinary least squares regression to estimate depressive symptoms and logistic regression to model the probability of clinically significant depression. RESULTS: African American men who were married/cohabiting only, employed only, or married/cohabiting, employed parents experienced lower levels of depressed mood, compared to African American women. Holding none of the roles under consideration in this study resulted in higher levels of depressive symptoms for African American women than for African American men. For diagnosable depression, the role combinations of married/cohabiting, employed and married/cohabiting, employed parent resulted in a lower probability of depression for African American men, compared to their female counterparts. Regardless of gender, role configurations that included employment produced the lowest levels of depressive symptoms and the lowest likelihood of clinically significant depression. CONCLUSIONS: Overall, the pattern of findings showed that role configurations are important in shaping mental health for both African American men and women. Multiple role combinations that included employment make individuals less vulnerable to depressive symptoms and clinically significant depression. Having no roles (e.g., unmarried, unemployed, non-parent) was more problematic for the well-being of African American women compared to African American men, but not as detrimental to African American mental health as prior studies focused on other racial and ethnic groups have suggested.