SCiEntifiC RepoRTs | (2018) 8:3398 | DOI:10.1038/s41598-018-21768-1
The novel dithiocarbamate, DpdtC
cancer cells by up-regulating
NDRG1 via inactivation of HER2-
ERK 1/2 signaling
, Youxun Liu
, Rui Guo
, Yun Fu
, Ziheng Zhang
, Pengfei Zhang
, Pingxin Zhou
, Tengfei Huang
, Xiaotong Li
& Changzheng Li
Dithiocarbamate has been tested for its eective anti-tumor activity, but the underlying mechanism
remains unclear. We previously prepared a novel diththiocarbamate derivative, DpdtC with an ability
of catalase inhibition. Here, we for the rst time investigated the growth inhibition eects of DpdtC on
HER2-amplied cancer cells and elucidated its mechanism of action. Results showed that DpdtC exerted
the potent anti-tumor eects against HER2-overexpressed SK-OV-3 and SK-BR-3 cells, especially on
SK-OV-3 cells with a higher NDRG1 level, which was also conrmed in the SK-OV-3 xenograft model.
Interestingly, we observed that NDRG1 was up-regulated, while membrane expression of HER2
was regressed in SK-OV-3 cells upon DpdtC treatment. In agreement, silencing endogenous NDRG1
also increased the expression of HER2 in SK-OV-3 cells, while overexpressing NDRG1 decreased
HER2 expression in SK-BR-3 cells. Furthermore, our results showed the formation of the EGFR/HER2
heterodimer was attenuated and phosphorylation of ERK1/2 was inhibited in SK-OV-3 cells when
treated with DpdtC. Collectively, these observations demonstrated that NDRG1 plays an important role
in mediating the inhibition eects of DpdtC in HER2-overexpressed cancer cells via selective targeting
of the HER2-ERK1/2 pathway. Hence, our investigation suggests that up-regulation of NDRG1 by DpdtC
is a promising therapeutic approach in HER2-overexpressed cancers.
Metal chelators are promising therapeutic agents that show marked and selective anti-tumor activity
. As we
know, cancer cells have an increased demand for iron and copper to maintain proper cell growth rate; therefore,
the use of chelators for cancer treatment has been an potential option
. e iron chelators such as di-2-pyridyl
ketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and desferrioxamine (DFO) have shown pronounced
inhibitory eects in several types of cancer
. Dithiocarbamates constitute a group of sulfur-containing com-
pounds with an eective chelating potency toward metal ions
, which can modulate the key molecules involved
in important processes, such as apoptosis, oxidative stress, transcription, and degradation of proteins
their molecular targets and mechanisms of action remain to be completely addressed.
NDRG1 belongs to the NDRG (N-myc downstream-regulated gene) family which has been reported to func-
tion as a tumor and metastasis suppressor gene in several types of cancer including breast, pancreatic and pros-
. Studies have shown that iron and copper chelators exhibited their anti-tumor eects through
up-regulating NDRG1 level to regress tumor growth and suppress metastasis
. Moreover, chelators such as
those of the dipyridyl thiosemicarbazone (DpT) class also exerted their metastasis-suppressive eects through
. In summary, NDRG1 may be a promising therapeutic target for the treatment of
School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.
College of Biomedical Engineering,
Xinxiang Medical University, Xinxiang, China.
School of Life Sciences, Xiamen University, Xiamen, China.
Correspondence and requests for materials should be addressed to Y.Y. (email: firstname.lastname@example.org) or C.L.
Received: 5 September 2017
Accepted: 6 February 2018
Published: xx xx xxxx