Induction of Tumor Cell Death through Targeting Tubulin and Evoking Dysregulation of Cell Cycle Regulatory Proteins by Multifunctional Cinnamaldehydes

Abstract

Multifunctional trans-cinnamaldehyde (CA) and its analogs display anti-cancer properties, with 2-benzoyloxycinnamaldehyde (BCA) and 5-fluoro-2-hydroxycinnamaldehyde (FHCA) being identified as the ortho-substituted analogs that possess potent anti-tumor activities. In this study, BCA, FHCA and a novel analog 5-fluoro-2-benzoyloxycinnamaldehyde (FBCA), were demonstrated to decrease growth and colony formation of human colon-derived HCT 116 and mammary-derived MCF-7 carcinoma cells under non-adhesive conditions. The 2-benzoyloxy and 5-fluoro substituents rendered FBCA more potent than BCA and equipotent to FHCA. The cellular events by which these cinnamaldehydes caused G2/M phase arrest and halted proliferation of HCT 116 cells were thereby investigated. Lack of significant accumulation of mitosis marker phospho-histone H3 in cinnamaldehyde-treated cells indicated that the analogs arrested cells in G2 phase. G2 arrest was brought about partly by cinnamaldehyde-mediated depletion of cell cycle proteins involved in regulating G2 to M transition and spindle assembly, namely cdk1, cdc25C, mad2, cdc20 and survivin. Cyclin B1 levels were found to be increased, which in the absence of active cdk1, would fail to drive cells into M phase. Concentrations of cinnamaldehydes that brought about dysregulation of levels of cell cycle proteins also caused tubulin aggregation, as evident from immunodetection of dose-dependent tubulin accumulation in the insoluble cell lysate fractions. In a cell-free system, reduced biotin-conjugated iodoacetamide (BIAM) labeling of tubulin protein pretreated with cinnamaldehydes was indicative of drug interaction with the sulfhydryl groups in tubulin. In conclusion, cinnamaldehydes treatment at proapoptotic concentrations caused tubulin aggregation and dysegulation of cell cycle regulatory proteins cdk1 and cdc25C that contributed at least in part to arresting cells at G2 phase, resulting in apoptotic cell death characterized by emergence of cleaved forms of caspase 3 and poly (ADP-ribose) polymerase (PARP). Results presented in this study have thus provided further insights into the intricate network of cellular events by which cinnamaldehydes induce tumor cell death.

Cinnamic aldehyde suppresses hypoxia-induced angiogenesis via inhibition of hypoxia-inducible factor-1α expression during tumor progression

“…In addition, we found that CA treatment suppresses tumor growth in mice and vessel formation in tumors. CA reduced HIF-1a and VEGF expression in cancer cells, and it has been reported to have antioxidant and anti-inflammatory actions [19][20][21][51][52][53]. These collective findings suggest that CA could be an effective cancer therapeutic agent through its orchestrated actions on apoptosis and angiogenesis in cancer and vascular endothelial cells.…”

Identification of toxicants in cinnamon-flavored electronic cigarette refill fluids

“…CAD is derived from the essential oil of cinnamon bark and is a highly bioactive compound serving many purposes (Jayaprakasha and Rao, 2011). It has been used as an anticancer agent (Nagle et al, 2012), an insecticide (Cheng et al, 2009), a fungicide (Bang et al, 2000;Shreaz et al, 2011), and a bactericide (Nostro et al, 2012). It is also used commercially as an additive in many foods and in fragrances (Cocchiara et al, 2005).…”

The Antisenescence Effect of Trans-Cinnamaldehyde on Adipose-Derived Stem Cells

“…It is a "Generally Regarded As Safe" molecule according to the Food and Drug Administration (1). Previous studies have suggested TC has antitumor activities (23). However, its antisenescence properties have not yet been investigated.…”