Abstract
Breast cancer is the most common cancer type and a primary cause of cancer mortality among females worldwide. Here, we analyzed the anticancer efficacy of a novel bromochlorinated monoterpene, PPM1, a synthetic analogue of polyhalogenated monoterpenes from Plocamium red algae and structurally similar non-brominated monoterpenes. PPM1, but not the non-brominated monoterpenes, decreased selectively the viability of several triple-negative as well as triple-positive breast cancer cells with different p53 status without significantly affecting normal breast epithelial cells. PPM1 induced accumulation of triple-negative MDA-MB-231 cells with 4N DNA content characterized by decreased histone H3-S10/T3 phosphorylation indicating cell cycle arrest in the G2 phase. Western immunoblot analysis revealed that PPM1 treatment triggered an initial rapid activation of Aurora kinases A/B/C and p21Waf1/Cip1 accumulation, which was followed by accumulation of polyploid >4N cells. Flow cytometric analysis showed mitochondrial potential disruption, caspase 3/7 activation, phosphatidylserine externalization, reduction of the amount polyploid cells, and DNA fragmentation consistent with induction of apoptosis. Cell viability was partially restored by the pan-caspase inhibitor Z-VAD-FMK indicating caspase contribution. In vivo, PPM1 inhibited growth, proliferation, and induced apoptosis in MDA-MB-231 xenografted onto the chick chorioallantoic membrane. Hence, Plocamium polyhalogenated monoterpenes and synthetic analogues deserve further exploration as promising anticancer lead compounds.
Highlights
Breast cancer is the most common cancer and the leading cause of cancer-related mortality among females world-wide accounting for 25% of all cancer cases and 15% of all cancer deaths in 2012 [1].In the United States, breast cancer is considered to be the most frequently diagnosed cancer type and the second main cause of cancer death in women
Considering the urgent need for effective and safe chemotherapeutic strategies for aggressive triple-negative breast cancer, we focused on polyhalogenated monoterpenes as potential oncological lead compounds
Only the brominated monoterpene PPM1, but not PPM2 or PPM3 (Figure 1a,b) decreased the viability of MDA-MB-231 Triple-negative breast cancer (TNBC) cells in a concentration- and time-dependent manner with IC50 values of 16 ± 2.2 μM, 7.3 ± 0.4 μM, and 3.3 ± 0.5 μM after 24 h, 48 h, and 72 h, respectively
Summary
Breast cancer is the most common cancer and the leading cause of cancer-related mortality among females world-wide accounting for 25% of all cancer cases and 15% of all cancer deaths in 2012 [1]. In the United States, breast cancer is considered to be the most frequently diagnosed cancer type and the second main cause of cancer death in women. By 2018, it is expected to account for 30% of all new cancer diagnoses and 14% of all estimated cancer deaths. Based on current incidence rates, 12.4% of US women will develop breast cancer during their lifetime [2]. Triple-negative breast cancer (TNBC) is characterized by the lack of expression of estrogen and progesterone receptors as well as the absence of overexpression of human EGF receptor 2 [3,4].
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