Omics' technologies have enabled clinicians to gain previously unprecedented insights into the molecular complexity and clinical heterogeneity of triple-negative breast cancer (TNBC). Increasingly it is being realized that TNBC does not respond well to current targeted therapies. This study aims to explore the antiproliferative effects and cancer regulatory mechanisms which underlie the drug resistance and aggressiveness of TNBC cells. Cryptocaryone (CPC) derived from Cryptocarya concinna demonstrated antiproliferative responses to TNBC cells (HCC1937 and MDA-MB-231), while normal breast cells (H184B5F5/M10) exhibited low cytotoxicity. In an in vivo assessment, CPC effectively reduced tumor growth in the MDA-MB-231 xenografted mouse model without significantly affecting body weight. Mechanistically, CPC triggered apoptosis, as indicated by an increase in sub-G1 and annexin V, as well as activated caspase 3 and 8. CPC also induced substantial oxidative stress by generating reactive oxygen species, mitochondrial superoxide, and membrane depolarization. CPC also induced oxidative DNA damage, as evidenced by the presence of γH2AX and 8-hydroxy-2-deoxyguanosine, in TNBC cells. All these CPC-induced changes were more pronounced in TNBC cells than normal cells. JNK and p38 MAPK inhibitors attenuate CPC-induced antiproliferation in TNBC cells. CPC upregulates phosphorylated JNK and p38 in TNBC cells. N-acetylcysteine pretreatment confirmed that oxidative stress plays a vital role in enhancing the antiproliferation, apoptosis, and DNA damage in TNBC cells. Moreover, the CPC-upregulated apoptosis and caspase 3/8 activations in TNBC cells were inhibited by JNK and p38 inhibitors. The impact of ERK activation on antiproliferation and apoptosis was evident in MDA-MB-231 cells, but not in HCC1937 cells. In conclusion, CPC demonstrated antiproliferative effects on TNBC cells through apoptosis and DNA damage induced by oxidative stress and MAPK activation, while showing drug safety in normal cells and breast cancer mouse model.
Chuang et al. (Sun,) studied this question.