Abstract
In ovarian cancer (OVCA), treatment failure due to chemo-resistance is a serious challenge. It is therefore critical to identify new therapies that are effective against resistant tumors and have reduced side effects. We recently identified 4-H-chromenes as tubulin depolymerizing agents that bind to colchicine site of beta-tubulin. Here, we screened a chemical library of substituted 4-H-chromenes and identified SP-6-27 to exhibit most potent anti-proliferative activity towards a panel of human cisplatin sensitive and resistant OVCA cell lines with 50% inhibitory concentration (IC50; mean ± SD) ranging from 0.10 ± 0.01 to 0.84 ± 0.20 μM. SP-6-27 exhibited minimum cytotoxicity to normal ovarian epithelia. A pronounced decrease in microtubule density as well as G2/M cell cycle arrest was observed in SP-6-27 treated cisplatin sensitive/resistant OVCA cells. The molecular mechanism of SP-6-27 induced cell death revealed modulation in cell-cycle regulation by upregulation of growth arrest and DNA damage inducible alpha transcripts (GADD45). An enhanced intrinsic apoptosis was observed in OVCA cells through upregulation of Bax, Apaf-1, caspase-6, -9, and caspase-3. In vitro wound healing assay revealed reduced OVCA cell migration upon SP-6-27 treatment. Additionally, SP-6-27 and cisplatin combinatorial treatment showed enhanced cytotoxicity in chemo-sensitive/resistant OVCA cells. Besides effect on cancer cells, SP-6-27 further restrained angiogenesis by inhibiting capillary tube formation by human umbilical vein endothelial cells (HUVEC). Together, these findings show that the chromene analog SP-6-27 is a novel chemotherapeutic agent that offers important advantages for the treatment of ovarian cancer.
Highlights
Ovarian cancer (OVCA) ranks fifth in the most prevalent cancer types in women with about 22,280 women diagnosed annually in the United States [1,2,3,4]
Besides effect on cancer cells, SP-6-27 further restrained angiogenesis by inhibiting capillary tube formation by human umbilical vein endothelial cells (HUVEC). These findings show that the chromene analog SP-6-27 is a novel chemotherapeutic agent that offers important advantages for the treatment of ovarian cancer
We investigated the effects of 4-H chromene analogs on the ovarian cancer cell viability
Summary
Ovarian cancer (OVCA) ranks fifth in the most prevalent cancer types in women with about 22,280 women diagnosed annually in the United States [1,2,3,4]. The standard OVCA treatment involving platinumbased chemotherapy often leads to the emergence of an unmanageable drug resistant phenotype [5,6]. There is an urgent need for new alternate drugs with more efficient therapeutic impact on OVCA, especially in treating chemo-resistant phenotypes. Targeted perturbation of microtubular dynamics represents the major therapeutic strategy to treat many types of cancers [9,10,11]. Microtubular inhibitors anti-cancer agents pose limitations of toxic side effects and emergence of multi-drug resistant phenotypes [12]. It is imperative to employ novel drug development approaches to design more effective microtubule targeting agents with fewer side effects [9,10, 13]
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