Cellular and molecular effects of protons: Apoptosis induction and potential implications for cancer therapy

Pietro, Cinzia Di; Piro, Salvatore; Tabbı̀, Giovanni; Ragusa, Marco; Pietro, Valentina Di; Zimmitti, Vincenzo; Cuda, Francesco; Anello, M.; Consoli, Ugo; Salinaro, Elisa Trovato; Caruso, Massimo; Vancheri, Carlo; Crimi, Nunzio; Sabini, M.G.; Cirrone, G.A.P.; Raffaele, L.; Privitera, Giuseppe; Pulvirenti, Alfredo; Giugno, Rosalba; Ferro, Alfredo; Cuttone, G.; Nigro, S. Ló; Purrello, Roberto; Purrello, Francesco; Purrello, Michele

doi:10.1007/s10495-005-3346-1

Cited by 71 publications

(63 citation statements)

References 49 publications

(37 reference statements)

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“…A recent report suggests that cell death induced by proton is apoptosis rather necrosis or autophagy (Di Pietro et al, 2006). In our result, cell death by proton is clearly apoptotic, i.e., nuclear DNA fragments and segregating pattern of nucleus shown in Figure 3A.…”

Section: Discussionsupporting

confidence: 67%

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Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases

Lee

Park

et al. 2008

Exp Mol Med

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Proton beam is useful to target tumor tissue sparing normal cells by allowing precise dose only into tumor cells. However, the cellular and molecular mechanisms by which proton beam induces tumor cell death are still undefined. We irradiated three different tumor cells (LLC, HepG2, and Molt-4) with low energy proton beam (35 MeV) with spread out Bragg peak (SOBP) in vitro, and investigated cell death by MTT or CCK-8 assay at 24 h after irradiation. LLC and HepG2 cells were sensitive to proton beam at over 10 Gy to induce apoptosis whereas Molt-4 showed rather low sensitivity. Relative biological effectiveness (RBE) values for the death rate relative to γ-ray were ranged from 1.1 to 2.3 in LLC and HepG2 but from 0.3 to 0.7 in Molt-4 at 11 d after irradiation by colony formation assay. The typical apoptotic nuclear DNA morphological pattern was observed by staining with 4'-6-diamidino-2-phenylindole (DAPI). Tiny fragmented DNA was observed in HepG2 but not in Molt-4 by the treatment of proton in apoptotic DNA fragment assay. By FACS analysis after stained with FITC-Annexin-V, early as well as median apoptotic fractions were clearly increased by proton treatment. Proton beam-irradiated tumor cells induced a cleavage of poly (ADP-ribose) polymerase-1 (PARP-1) and procaspases-3 and -9. Activity of caspases was highly enhanced after proton beam irradiation. Reactive oxygen species (ROS) were significantly increased and N-acetyl cysteine pretreatment restored the apoptotic cell death induced by proton beam. Furthermore, p38 and JNK but not ERK were activated by proton and dominant negative mutants of p38 and JNK revived proton-induced apoptosis, suggesting that p38 and JNK pathways may be activated through ROS to activate apoptosis. In conclusion, our data clearly showed that single treatment of low energy proton beam with SOBP increased ROS and induced cell death of solid tumor cells (LLC and HepG2) in an apoptotic cell death program by the induction of caspases activities.

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Section: Discussionsupporting

confidence: 67%

“…Cell death induced by proton beam is identified as apoptosis (Di Pietro et al, 2006). The study investigated that genes involved in various phases of apoptosis are checked by RT-PCR and used LET instead of SOBP of proton beam.…”

Section: Introductionmentioning

confidence: 99%

Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases

Lee

Park

et al. 2008

Exp Mol Med

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“…Bmi-1 -/ -mice are known to have increased levels of ROS and hydroxyl free radicals that are produced by oxidative stress, which subsequently results in an increase in DNA double strand breaks (32). The present results demonstrated that the PQQ-supplemented diet decreased the number of BKO-induced double strand DNA breaks in the liver.…”

Section: Effects Of Pqq On the Ros Levels In The Liver Of Bmi-1supporting

confidence: 58%

Biological effects of pyrroloquinoline quinone on liver damage in Bmi-1 knockout mice

Huang

Chen

Miao

2015

Experimental and Therapeutic Medicine

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Abstract. Pyrroloquinoline quinone (PQQ) has been demonstrated to function as an antioxidant by scavenging free radicals and subsequently protecting the mitochondria from oxidative stress-induced damage. The aim of the present study was to investigate whether PQQ is able to rescue premature senescence in the liver, induced by the deletion of B cell-specific Moloney MLV insertion site-1 (Bmi-1), by inhibiting oxidative stress. In vivo, the mice were allocated into three groups that underwent the following treatment protocols. WT mice received a normal diet, while BKO mice also received a normal diet. An additional group of BKO mice were fed a PQQ-supplemented diet (BKO + PQQ; 4 mg PQQ/kg in the normal diet). The results indicated that PQQ partially rescued the liver damage induced by the deletion of Bmi-1. PQQ was demonstrated to exhibit these therapeutic effects on liver damage through multiple aspects, including the promotion of proliferation, antiapoptotic effects, the inhibition of senescence, the upregulation of antioxidant ability, the downregulation of cell cycle protein expression, the scavenging of reactive oxygen species and the reduction of DNA damage. The results of these experiments indicated that treatment of BKO mice with a moderate dose of PQQ significantly protected the liver from deleterious effects by inhibiting oxidative stress and participating in DNA damage repair. Therefore, PQQ has great potential as a therapeutic agent against oxidative stress during liver damage. IntroductionThe liver is a unique organ that is usually silent under physiological conditions; however, the organ exhibits regenerative properties following damage and/or parenchymal loss (1). In previous years, hepatic disease and the associated morbidity rates have increased year by year, with the condition becoming a major global health care problem (2). A previous study demonstrated that reactive oxygen species (ROS) may be a cause of liver damage, which is characterized by a progression from steatosis to chronic hepatitis, cirrhosis and hepatocellular carcinoma (3). Although studies have attempted to identify efficient liver therapeutics from herbal origins, a number of the potential candidates have not been well characterized and require further investigation (4).Over 50 years ago, Harman proposed the free radical or oxidative stress theory of aging (5). The author hypothesized that free radicals and/or ROS are produced endogenously from normal cellular metabolic processes. In this theory, an imbalance between ROS and antioxidants can lead to oxidative stress, which subsequently damages various macromolecules. An increasing body of evidence has demonstrated that an increased production of ROS plays an important role in the development of various age-associated diseases (6).B cell-specific Moloney MLV insertion site-1 (Bmi-1) belongs to the Polycomb group of genes, which are transcriptional repressors that are essential for the maintenance of appropriate gene expression patterns during development (7). The premature deletio...

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“…Apoptosis contributes to tumor growth kinetics and response to radiotherapy, and some radiosensitive tumors have a tendency to undergo apoptosis [14]. There may be differences in the kinetics and extent of apoptosis induction between protons and photon [15,16]. Gerelchuluun et al showed greater induction of in situ DNA double-strand breaks and apoptosis by proton beams in the early phase after irradiation, compared with photon beams.…”

Section: Biological Characteristicsmentioning

confidence: 99%

The use of proton-beam therapy in the treatment of non-small-cell lung cancer

Oshiro¹,

Sakurai

2013

Expert Review of Medical Devices

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Cellular and molecular effects of protons: Apoptosis induction and potential implications for cancer therapy

Cited by 71 publications

References 49 publications

Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases

Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases

Biological effects of pyrroloquinoline quinone on liver damage in Bmi-1 knockout mice

The use of proton-beam therapy in the treatment of non-small-cell lung cancer

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