A novel curcumin-like dienone induces apoptosis in triple-negative breast cancer cells

Abstract

Purpose According to the World Health Organization (WHO), breast cancer is the most common cancer affecting women worldwide. In the USA ~12.3 % of all women are expected to be diagnosed with various types of breast cancer, exhibiting varying degrees of therapeutic response rates. Therefore, the identification of novel anti-breast cancer drugs is of paramount importance. Methods The 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore was incorporated into a number of cytotoxins. Three of the resulting dienones, 2a, 2b and 2c, were tested for their antineoplastic potencies in a variety of human breast cancer-derived cell lines, including the triple negative MDA-MB-231 cell line and its metastatic variant, using a live-cell bio-imaging method. Special emphasis was put on dienone 2c, since its anti-cancer activity and its mode of inflicting cell death have so far not been reported. Results We found that all three dienones exhibited potent cytotoxicities towards the breast cancer-derived cell lines tested, whereas significantly lower toxicities were observed towards the non-cancerous human breast cell line MCF-10A. The dienones 2b and 2c exhibited the greatest selective cytotoxicity at submicromolar concentration levels. We found that these two dienones induced phosphatidylserine externalization in MDA-MB-231 cells in a concentration-dependent manner, suggesting that their cytotoxic effect might be mediated by apoptosis. This possibility was confirmed by our observation that the dienone 2c can induce mitochondrial depolarization, caspase-3 activation, cell cycle disruption and DNA fragmentation in MDA-MB-231 cells. Conclusion Our findings indicate that dienone 2c uses the mitochondrial/intrinsic pathway to inflict apoptosis in triple negative MDA-MB-231 breast cancer-derived cells. This observation warrants further assessment of dienone 2c as a potential anti-breast cancer drug.

Synthesis and bioactivities of halogen bearing phenolic chalcones and their corresponding bis Mannich bases

“…Selectivity index (SI) figures were generated which are quotient of the average CC 50 figure of a compound toward a spesific cell line. The results in Table 1 reveal that SI values of greater than 1 were obtained and thus all compounds synthesized are tumorspecific antineoplastic agents 38 . The average selectivity index figures revealed that morpholine containing Mannich bases 1b (with fluorine), 2b (with chlorine), and 3b (with bromine) had the highest average SI values comparing to the amines piperidine and N-methylpiperazine.…”

Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones

“…The following controls were used: 1 mM H 2 O 2 as a positive control, 1% v/v DMSO as a vehicle control, and untreated cells as a negative control. The selective cytotoxicity index (SCI) was calculated using the following equation: IC 50 of non-cancerous cells / IC 50 of cancer cells [30]. The SCI indicates the selective profile that a drug exhibits towards cancer cells.…”

“…Previously, we reported the development of several new cancer drugs and screening methods [29, 30]. We found, among others, that compounds containing the piperidone structure are highly cytotoxic, and that the P2 piperidone compound exhibits a potent anti-neoplastic activity against breast cancer cells [30, 31].…”

“…We found, among others, that compounds containing the piperidone structure are highly cytotoxic, and that the P2 piperidone compound exhibits a potent anti-neoplastic activity against breast cancer cells [30, 31]. Next to P2, we generated additional analogs with the intention of increasing the anti-cancer potency of P2.…”

A novel class of piperidones exhibit potent, selective and pro-apoptotic anti-leukemia properties

“…Hoechst stain is a blue fluorescent dye that may easily cross cell membranes of healthy and dead cells, and stains nuclear DNA, thus identifying the total number of cells (27). PI (red) only stains cells with compromised plasma membrane, thus indicating the number of dead cells (28). The fluorescence signals emitted by the stained cell nuclei were captured in two separate channels, in fulfillment with each individual fluorophore emission requirements (27).…”