Synthesis, cytotoxicity and apoptosis of naphthalimide polyamine conjugates as antitumor agents

Tian, Zhiyong; Xie, Songqiang; Du, Yaowu; Ma, Yuanfang; Zhao, Jin; Gao, Wenyuan; Wang, Chaojie

doi:10.1016/j.ejmech.2008.02.044

Cited by 61 publications

(49 citation statements)

References 19 publications

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“…It is reported that bisnaphthalimidopropyl spermidine (BNIPSpd) induces apoptosis within promyelocytic leukaemia cells (HL60) (21) as well as colon carcinoma cells (Caco-2 and HT-29) exhibiting DNA fragmentation, elevated caspase-3 activity and apoptotic bodies (10). MNIHspd was able to kill B16 cells via both mitochondrial and cellular membrane death receptor apoptosis pathways (15), and another naphthalimidepolyamine conjugate induced apoptosis in hepatoma HepG2 cells via a mitochondrial pathway (22). These reports indicate that naphthalimide polyamine conjugates exhibit different apoptotic mechanisms in an agent-and cell-typespecific manner.…”

Section: Discussionmentioning

confidence: 99%

“…However, mononaphthalimide polyamine conjugates were seldom reported compared to their bisnaphthalimide counterparts. In our laboratory, we developed a group of mononaphthalimide polyamine conjugates with both natural and synthetic polyamine moieties exhibiting potent cytotoxic effect on several tested tumor cell lines and better cell selectivity against human hepatoma BEL-7402 (IC 50 =1.06 μM) and human normal hepatocyte QSG-7701 (IC 50 >50 μM), including homospermidine-mononaphthalimide (MNIHspd) conjugation and mononaphthalimide-spermidine (MNISpd) conjugate (15). Further, mononaphthalimide homospermidine conjugate was able to induce apoptosis in B16 cells (15).…”

Section: Introductionmentioning

confidence: 99%

“…In our laboratory, we developed a group of mononaphthalimide polyamine conjugates with both natural and synthetic polyamine moieties exhibiting potent cytotoxic effect on several tested tumor cell lines and better cell selectivity against human hepatoma BEL-7402 (IC 50 =1.06 μM) and human normal hepatocyte QSG-7701 (IC 50 >50 μM), including homospermidine-mononaphthalimide (MNIHspd) conjugation and mononaphthalimide-spermidine (MNISpd) conjugate (15). Further, mononaphthalimide homospermidine conjugate was able to induce apoptosis in B16 cells (15). In fact, apoptotic mechanisms have been exploited for anti-tumor therapy as it seems to be clearly advantageous to the organism (16), and the apoptotic mechanism induced by MNISpd remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Reactive oxygen species (ROS) accumulation induced by mononaphthalimide-spermidine leads to intrinsic and AIF-mediated apoptosis in HeLa cells

Zhao

2011

Oncol Rep

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Abstract. Developing polyamine conjugates having the potential of transporting naphthalimide selectively into tumor cells is attractive. However, the evaluation of their cytotoxic mechanism has not been comprehensive. This study focused on the effects of mononaphthalimide spermidine (MNISpd) conjugate on apoptosis induction and the relationship between MNISpd-induced apoptosis and reactive oxygen species (ROS) in HeLa cells. Our findings indicated that 9 μM MNISpd induced apoptosis in HeLa cells during a 48-h period. MNISpd induced apoptosis in HeLa cells following cytochrome c release, elevation of caspase 3/9 activity, apoptosisinducing factor (AIF) translocation and up-/down-regulation of Bax/Bcl-2 protein expression, respectively, and these effects were completely antagonized by pre-incubation with 10 mM NAC for 2 h. MNISpd induced significant ROS accumulation following up-regulation of polyamine oxidase (PAO) activity and complex variations in glutathione levels. It is concluded that MNISpd-induced apoptosis is related to intrinsic caspase-dependent and AIF-mediated caspaseindependent apoptosis pathways in HeLa cells. MNISpdinduced apoptosis correlates to MNISpd-induced ROS production resulting from GSH (reduced form of glutathione) pool depletion, and PAO is likely to be the source of ROS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reactive oxygen species (ROS) accumulation induced by mononaphthalimide-spermidine leads to intrinsic and AIF-mediated apoptosis in HeLa cells

Zhao

2011

Oncol Rep

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“…Our previous data demonstrated that some polyamine conjugates, such as naphthalimide, anthracene and anthraquinone, could be uptaked by tumor cells via polyamine transporter and could exert potent antitumor effects [16,17]. It is supposed that down-regulated intracellular polyamine level by NSAIDs could facilitate the uptake of polyamine naphthalimide conjugate.…”

Section: Introductionmentioning

confidence: 99%

COX-2-independent induction of apoptosis by celecoxib and polyamine naphthalimide conjugate mediated by polyamine depression in colorectal cancer cell lines

Xie

Zhang

et al. 2011

Int J Colorectal Dis

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“…In recent years, we found that some naphthalimide derivatives displayed potent inhibitive effects on HCC. For example, the naphthalimides conjugated with polyamines have been designed to improve their efficacy against HCC with reduced adverse effects [4,5]. Previous report demonstrated that the conjugates of naphthalimide and alkylating agent were more effective than their respective naphthalimide and alkylating agent in S-180 and Ehrlich ascites carcinoma models [6].…”

Section: Introductionmentioning

confidence: 99%

3-Nitro-naphthalimide and nitrogen mustard conjugate NNM-25 induces hepatocellular carcinoma apoptosis via PARP-1/p53 pathway

Xie

Zhang

et al. 2012

Apoptosis

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Hepatocellular carcinoma (HCC) is one of the main causes of death in cancer. Some naphthalimide derivatives exert high anti-proliferative effects on HCC. In this study, it is confirmed that 3-nitro-naphthalimide and nitrogen mustard conjugate (NNM-25), a novel compound conjugated by NNM-25, displayed more potent therapeutic action on HCC, both in vivo and in vitro, than amonafide, a naphthalimide drug in clinical trials. More importantly, preliminary toxicological evaluation also supported that NNM-25 exhibited less systemic toxicity than amonafide at the therapeutic dose. The antitumor mechanism of conjugates of naphthalimides with nitrogen mustard remains poorly understood up to now. Here, we first reported that apoptosis might be the terminal fate of cancer cells treated with NNM-25. Inhibition of p53 by siRNA resulted in a significant decrease of NNM-25-induced apoptosis, which corroborated that p53 played a vital role in the cell apoptosis triggered by NNM-25. NNM-25 inhibited the PARP-1 activity, AKT phosphorylation, up-regulated the protein expression of p53, Bad, and mTOR as well as down-regulating the protein expression of Bcl-2 and decreasing mitochondrial membrane potential. It also facilitated cytochrome c release from mitochondria to cytoplasm, activated caspase 8, caspase 9, and caspase 3 in HepG2 cells in vitro, as also authenticated in H22 tumor-bearing mice in vivo. Collectively, the conjugation of naphthalimides with nitrogen mustard provides favorable biological activity and thus is a valuable strategy for future drug design in HCC therapy.

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Synthesis, cytotoxicity and apoptosis of naphthalimide polyamine conjugates as antitumor agents

Cited by 61 publications

References 19 publications

Reactive oxygen species (ROS) accumulation induced by mononaphthalimide-spermidine leads to intrinsic and AIF-mediated apoptosis in HeLa cells

Reactive oxygen species (ROS) accumulation induced by mononaphthalimide-spermidine leads to intrinsic and AIF-mediated apoptosis in HeLa cells

COX-2-independent induction of apoptosis by celecoxib and polyamine naphthalimide conjugate mediated by polyamine depression in colorectal cancer cell lines

3-Nitro-naphthalimide and nitrogen mustard conjugate NNM-25 induces hepatocellular carcinoma apoptosis via PARP-1/p53 pathway

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