A Novel Polyhalogenated Monoterpene Induces Cell Cycle Arrest and Apoptosis in Breast Cancer Cells

Mar Drugs. 2019 Jul 25;17(8):437. doi: 10.3390/md17080437.


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.

Keywords: Plocamium; apoptosis; cell cycle; chick chorioallantoic membrane assay; polyhalogenated monoterpenes; red algae.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Breast / drug effects
  • Breast / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Caspase Inhibitors / pharmacology
  • Caspases / metabolism
  • Cell Cycle Checkpoints / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Female
  • G2 Phase / drug effects
  • Histones / metabolism
  • Humans
  • MCF-7 Cells
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Monoterpenes / pharmacology*
  • Plocamium / chemistry
  • Rhodophyta / chemistry


  • Antineoplastic Agents
  • Caspase Inhibitors
  • Histones
  • Monoterpenes
  • Caspases