Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells

Arango, Diego; Wilson, Andrew J.; Shi, Qiuhu; Corner, Georgia; Aranes, Maria; Nicholas, Courtney; Lesser, Martin; Mariadason, John M.; Augenlicht, Leonard H.

doi:10.1038/sj.bjc.6602215

Cited by 226 publications

(190 citation statements)

References 42 publications

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“…So, we utilized HCT116 Bax wildtype and null isogenic cell lines to test our hypothesis. Earlier characterisation of HCT116 cell lines indicated that cells lacking Bax are resistant to TRAIL and are significantly less sensitive to chemotherapy (Zhang et al, 2000;Arango et al, 2004). In contrast to Bax wild-type colorectal cancer cell lines, we found that FLIP silencing did not induce cell death in HCT116 cells lacking Bax.…”

Section: Discussioncontrasting

confidence: 55%

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

et al. 2008

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Death receptors can directly (type I cells) or indirectly induce apoptosis by activating mitochondrial-regulated apoptosis (type II cells). The level of caspase 8 activation is thought to determine whether a cell is type I or II, with type II cells less efficient at activating this caspase following death receptor activation. FLICE-inhibitory protein (FLIP) blocks death receptor-mediated apoptosis by inhibiting caspase 8 activation; therefore, we assessed whether silencing FLIP could convert type II cells into type I. FLIP silencing-induced caspase 8 activation in Bax wild-type and null HCT116 colorectal cancer cells; however, complete caspase 3 processing and apoptosis were only observed in Bax wild-type cells. Bax-null cells were also more resistant to chemotherapy and tumor necrosis factor-related apoptosis inducing ligand and, unlike the Bax wild-type cells, were not sensitized to these agents by FLIP silencing. Further analyses indicated that release of second mitochondrial activator of caspases from mitochondria and subsequent inhibition of X-linked inhibitor of apoptosis protein (XIAP) was required to induce full caspase 3 processing and apoptosis following FLIP silencing. These results indicate that silencing FLIP does not necessarily bypass the requirement for mitochondrial involvement in type II cells. Furthermore, targeting FLIP and XIAP may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis.

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Section: Discussioncontrasting

confidence: 55%

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

et al. 2008

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“…The factors determining a p53-dependent apoptotic or cytostatic response to cytotoxic insult remain unclear. Recently, elevated cMyc levels have been identified as one such factor favouring a p53-dependent apoptotic response (Seoane et al, 2002 Despite significant progress in the identification of markers predicting response to other chemotherapeutic agents commonly used in the treatment of colorectal malignancies, namely, 5FU and oxaliplatin (Augenlicht et al, 1997;Salonga et al, 2000;Arango et al, , 2003Park et al, 2001;Shirota et al, 2001), there is a great need for clinical predictors of response to camptothecin derivatives. The capability of predicting response to the chemotherapeutic agents available for the treatment of colorectal cancer would allow tailoring of treatment to individual patients, thus maximising the probability of optimal response to therapy.…”

Section: Discussionmentioning

confidence: 99%

“…The camptothecin derivative has been shown to be a useful chemotherapeutic agent for the treatment of colorectal cancer patients, improving response rates and survival when used in combination with 5FU, and has also been shown to be effective in 5FU-resistant tumours (Cunningham et al, 1998;Douillard et al, 2000;. Recently, there has been significant progress in the identification of genetic markers that allow prediction of response to 5FU and/or oxaliplatin, which together with CPT-11 are the main chemotherapeutic agents used in the treatment of colorectal cancer (Augenlicht et al, 1997;Salonga et al, 2000;Arango et al, , 2003Park et al, 2001;Shirota et al, 2001). However, there is great need for markers predicting the efficacy of CPT-11 treatment.…”

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confidence: 99%

c-Myc overexpression sensitises colon cancer cells to camptothecin-induced apoptosis

et al. 2003

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The proto-oncogene c-Myc is overexpressed in 70% of colorectal tumours and can modulate proliferation and apoptosis after cytotoxic insult. Using an isogenic cell system, we demonstrate that c-Myc overexpression in colon carcinoma LoVo cells resulted in sensitisation to camptothecin-induced apoptosis, thus identifying c-Myc as a potential marker predicting response of colorectal tumour cells to camptothecin. Both camptothecin exposure and c-Myc overexpression in LoVo cells resulted in elevation of p53 protein levels, suggesting a role of p53 in the c-Myc-imposed sensitisation to the apoptotic effects of camptothecin. This was confirmed by the ability of PFT-a, a specific inhibitor of p53, to attenuate camptothecin-induced apoptosis. p53 can induce the expression of p21 Waf1/Cip1 , an antiproliferative protein that can facilitate DNA repair and drug resistance. Importantly, although camptothecin treatment markedly increased p21 Waf1/Cip1 levels in parental LoVo cells, this effect was abrogated in c-Mycoverexpressing derivatives. Targeted inactivation of p21 Waf1/Cip1 in HCT116 colon cancer cells resulted in significantly increased levels of apoptosis following treatment with camptothecin, demonstrating the importance of p21 Waf1/Cip1 in the response to this agent. Finally, cDNA microarray analysis was used to identify genes that are modulated in expression by c-Myc upregulation that could serve as additional markers predicting response to camptothecin. Thirty-four sequences were altered in expression over four-fold in two isogenic c-Myc-overexpressing clones compared to parental LoVo cells. Moreover, the expression of 10 of these genes was confirmed to be significantly correlated with response to camptothecin in a panel of 30 colorectal cancer cell lines.

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“…The apoptotic pathway of colon cancer cells after exposure to oxaliplatin involves caspase 3 activation, translocation of Bax in the mitochondria, and release of cytochrome C in the cytosol 8 .…”

Section: Dna Lesionsmentioning

confidence: 99%

Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

2011

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molecularly targeted anticancer therapy with conventional cytotoxic chemotherapy. Such combinations can come about only through rational design of clinical trials, taking into account the pharmacology and clinical development of the drugs involved. It is therefore worthwhile revisiting classical chemotherapy agents, because this renewed knowledge could provide a foundation for future trials.Oxaliplatin is the newest platinum derivative in standard chemotherapy. Here, we review oxaliplatin from the pharmacologic and drug development perspectives, and we comment on possible associations of this drug with molecularly targeted therapy. CHEMICAL AND PHYSICAL PROPERTIES AND BIOTRANSFORMATIONOxaliplatin differs from cisplatin in that the amine groups of cisplatin are replaced by diaminocyclohexane (dach). The molecular weight of oxaliplatin is 397.3. It is slightly soluble in water, less so in methanol, and almost insoluble in ethanol and acetone 1 . Its full chemical name, oxalato(transl-1,2-diaminocyclohexane)platinum, refers to the presence of an oxalate "leaving group" and the dach carrier ligand, which are responsible, at least in part, for its unique properties 2,3 . For example, unlike cisplatin, oxaliplatin in plasma rapidly undergoes non-enzymatic transformation into reactive compounds because of displacement of the oxalate group, a process that complicates its pharmacokinetic profile. Most of the compounds appear to be pharmacologically inactive, but dichloro(dach) platinum complexes enter the cell, where they have cytotoxic properties. MECHANISMS OF ACTIONVarious mechanisms of action are ascribed to oxaliplatin. Like other platinum-based compounds, oxaliplatin exerts its cytotoxic effect mostly through dna damage. Apoptosis of cancer cells can be caused by formation of dna lesions, arrest of dna synthesis, ABSTRACT ObjectiveTo review preclinical and clinical data for oxaliplatin in the current context of molecularly targeted therapy.

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Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells

Cited by 226 publications

References 42 publications

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

c-Myc overexpression sensitises colon cancer cells to camptothecin-induced apoptosis

Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

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