Photodynamic therapy-induced death of HCT 116 cells: Apoptosis with or without Bax expression

Chiu, Song Mao; Xue, Liang; Azizuddin, Kashif; Oleinick, Nancy L.

doi:10.1007/s10495-005-2217-0

Cited by 30 publications

(18 citation statements)

References 29 publications

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“…In an HCT116 Bax knockdown line, apoptosis proceeded without caspase-3 activation, but this phenomenon was also observed in wild-type HCT116. 5 This is not the case with L1210 cells, where procaspase-3 cleavage and DEVDase activation occurs within minutes of photodamage. 7 Irradiation of HeLa cells photosensitizer with hypericin was also found to initiate autophagy, but only if both Bax and Bak were silenced.…”

Section: Quantitation Of Autophagymentioning

confidence: 99%

“…The responsiveness of the Bax knockdown is consistent with reports by Oleinick's group showing that absence of Bax, or of procaspase-3, did not protect cells from phototoxic effects of PDT using the phthalocyanine photosensitizer Pc 4. [3][4][5][6] Time sequence of autophagy and apoptosis A typical result after exposure of L1210 cells to an LD 90 PDT dose of CPO is shown in Fig. 5.…”

Section: Apoptotic and Cytotoxic Response To Pdtmentioning

confidence: 99%

“…2 It was later proposed that apoptosis was a means for the disposing of dead cells, but was not necessary for expression of the cytotoxic effects of PDT. [3][4][5][6] We originally proposed that the initiation of apoptosis by PDT, using a porphycene photosensitizing agent, derived from direct mitochondrial photodamage. 7 Later work revealed that the initial target of many photosensitizing agents was the anti-apoptotic protein Bcl-2, 8,9 a finding confirmed by Oleinick's group.…”

Section: Introductionmentioning

confidence: 99%

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Apoptotic and autophagic responses to Bcl-2 inhibition and photodamage

Kessel

Arroyo

2007

Photochem Photobiol Sci

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Among the cellular responses to photodamage initiated by photodynamic therapy (PDT) are autophagy and apoptosis. While autophagy is a reversible process that can be both a survival and a death pathway, apoptosis is irreversible, leading only to cell death. In this study, we followed the fate of mouse leukemia L1210 cells after photodamage to the endoplasmic reticulum (ER) using a porphycene photosensitizer, where Bcl-2 was among the PDT targets. In wild-type cells, we observed a rapid wave of autophagy, presumed to represent the recycling of some damaged organelles, followed by apoptosis. Using shRNA technology, we created a Bax knockdown line (L1210/Bax − ). In the latter cell line, we found a marked decrease in apoptosis after photodamage or pharmacologic inactivation of Bcl-2 function, but this did not affect PDT efficacy. Loss of viability was associated with a highly-vacuolated morphology consistent with autophagic cell death. Previous studies indicated pro-survival attributes of autophagy after low-dose PDT, suggesting that autophagy may be responsible for the 'shoulder' on the dose-response curve. It appears that attempts at extensive recycling of damaged organelles are associated with cell death, and that this phenomenon is amplified when apoptosis is suppressed.

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Section: Quantitation Of Autophagymentioning

confidence: 99%

Section: Apoptotic and Cytotoxic Response To Pdtmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Apoptotic and autophagic responses to Bcl-2 inhibition and photodamage

Kessel

Arroyo

2007

Photochem Photobiol Sci

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“…The photosensitizer hypericin reportedly detaches hexokinase from mitochondria (Miccoli et al, 1998), whereas the phthalocyanine photosensitizer Pc 4 causes the photochemical destruction of Bcl-2 (Xue et al, 2001). Altogether, available data suggest that photosensitizing agents can target mitochondria, where they induce apoptosis independently from the p53 status, even in Bax-negative cells (Chiu et al, 2005).…”

Section: Chemotherapy and Mitochondriamentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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“…Oleinick's group reported that PDT-induced cell death in the Bax-deficient DU145 prostate cell line 5 and a Bax knock-out HCT116 cells line 17 was neither necrotic nor apoptotic. 5 We found that DU145 cells were killed by PDT protocols employing the ER photosensitizer CPO without development of apoptotic morphological features, loss of mitochondrial potential, formation of condensed nuclear chromatin or the activation of pro-caspases 3/7.…”

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confidence: 99%

Initiation of apoptosis and autophagy by photodynamic therapy

2006

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This study was designed to examine modes of cell death after photodynamic therapy (PDT). Murine leukemia L1210 cells and human prostate Bax-deficient DU-145 cells were examined after PDTinduced photodamage to the endoplasmic reticulum (ER). Previous studies indicated that this treatment resulted in a substantial loss of Bcl-2 function. Both apoptosis and autophagy occurred in L1210 cells after ER photodamage with the latter predominating after 24 hr. These processes were characterized by altered cellular morphology, chromatin condensation, loss of mitochondrial membrane potential and formation of vacuoles containing cytosolic components. Western blots demonstrated processing of LC3-I to LC3-II, a marker for autophagy. In DU145 cells, PDT initiated only autophagy. Phosphatidylinositol (PI) 3-kinase inhibitors suppressed autophagy in both cell lines as indicated by inhibition of vacuolization and LC3 processing. Inhibitors of apoptosis and/or autophagy were then used to delineate the contributions of the two pathways to the effects of PDT. Given the ability of autophagy to upregulate MHC-11 peptide presentation, autophagy may play a role in the ability of photodynamic therapy to stimulate immunologic recognition of target cells. Keywords apoptosis; autophagy; photodynamic therapyPhotodynamic therapy (PDT) involves the photosensitization of neoplastic cells and tissues with porphyrins or related structures that catalyze, upon irradiation, formation of reactive oxygen species. 1 While effects of PDT on tissues also include vascular shutdown and the evoking of immunologic responses, there is also an element of direct cell kill that can reduce the neoplastic cell population by 2-3 logs. 1 This might be useful in a surgical context since it has been estimated that tumor cells are often left at surgical margins. 2 It was initially believed that PDT killed cells via necrosis, and in 1991, Oleinick's group demonstrated that PDT could trigger the induction of apoptosis. 3 Numerous subsequent studies documented the induction of apoptosis in a variety of cell types, by an array of different sensitizers and a variety of mechanisms. The cytotoxicity of PDT protocols, however, cannot be fully explained by the apoptotic response. Cells lacking procaspase-3 4 or Bax 5 die after PDT, but do not display the characteristics of necrotic or apoptotic cell death.Autophagy was originally characterized as a survival response to nutrient deprivation and other forms of cellular stress, 6 but studies within the past decade clearly indicate that the induction of autophagy can sometimes lead to cell death. [7][8][9][10][11][12][13] Indeed, autophagic death is important during

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Photodynamic therapy-induced death of HCT 116 cells: Apoptosis with or without Bax expression

Cited by 30 publications

References 29 publications

Apoptotic and autophagic responses to Bcl-2 inhibition and photodamage

Apoptotic and autophagic responses to Bcl-2 inhibition and photodamage

Mitochondria as therapeutic targets for cancer chemotherapy

Initiation of apoptosis and autophagy by photodynamic therapy

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