Interferon potentiates antiproliferative activity of CPT-11 against human colon cancer xenografts

Ohwada, Susumu; Kobayashi, Isao; Maemura, Michio; Satoh, Yoshihiro; Ogawa, Tetsushi; Iino, Yuichi; Morishita, Yasuo

doi:10.1016/s0304-3835(96)04477-1

Cited by 20 publications

(15 citation statements)

References 7 publications

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“…The combined treatment also reduced tumour cell proliferation. In agreement with previous data (Ohwada et al, 1996;Xu and Villalona-Calero, 2002), we found that SN-38 alone markedly inhibited HT-29 cell proliferation by arresting cells mainly at the G2/M phase and, to a lesser extent, at the S phase. AS602868 for its part only induced a modest arrest at the S phase, but in combination with SN38 increased the number of cells in both S and G2/M phases.…”

Section: Discussionsupporting

confidence: 93%

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

et al. 2008

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NF-kB interferes with the effect of most anti-cancer drugs through induction of anti-apoptotic genes. Targeting NF-kB is therefore expected to potentiate conventional treatments in adjuvant strategies. Here we used a pharmacological inhibitor of the IKK2 kinase (AS602868) to block NF-kB activation. In human colon cancer cells, inhibition of NF-kB using 10 mM AS602868 induced a 30 -50% growth inhibitory effect and strongly enhanced the action of SN-38, the topoisomerase I inhibitor and CPT-11 active metabolite. AS602868 also potentiated the cytotoxic effect of two other antineoplasic drugs: 5-fluorouracil and etoposide. In xenografts experiments, inhibition of NF-kB potentiated the antitumoural effect of CPT-11 in a dose-dependent manner. Eighty-five and 75% decreases in tumour size were observed when mice were treated with, respectively, 20 or 5 mg kg À1 AS602868 associated with 30 mg kg À1 CPT-11 compared to 47% with CPT-11 alone. Ex vivo tumour analyses as well as in vitro studies showed that AS602868 impaired CPT-11-induced NF-kB activation, and enhanced tumour cell cycle arrest and apoptosis. AS602868 also enhanced the apoptotic potential of TNFa on HT-29 cells. This study is the first demonstration that a pharmacological inhibitor of the IKK2 kinase can potentiate the therapeutic efficiency of antineoplasic drugs on solid tumours.

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Section: Discussionsupporting

confidence: 93%

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

et al. 2008

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“…For example, treatment with camptothecin leads to an increase in the level of ISG15 mRNA (55). Furthermore, treatment with both IFNs and camptothecin causes synergistic killing of colorectal cancer xenografts in nude mice (56). In order to clarify the role of ISG15 in tumor suppression, it is essential to identify target proteins that are ISGylated in response to chemotherapeutic drugs.…”

Section: Resultsmentioning

confidence: 99%

Chemosensitivity is controlled by p63 modification with ubiquitin-like protein ISG15

Jeon

Jo²,

Yoo³

et al. 2012

J. Clin. Invest.

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Identification of the cellular mechanisms that mediate cancer cell chemosensitivity is important for developing new cancer treatment strategies. Several chemotherapeutic drugs increase levels of the posttranslational modifier ISG15, which suggests that ISGylation could suppress oncogenesis. However, how ISGylation of specific target proteins controls tumorigenesis is unknown. Here, we identified proteins that are ISGylated in response to chemotherapy. Treatment of a human mammary epithelial cell line with doxorubicin resulted in ISGylation of the p53 family protein p63. An alternative splice variant of p63, ΔNp63α, suppressed the transactivity of other p53 family members, and its expression was abnormally elevated in various human epithelial tumors, suggestive of an oncogenic role for this variant. We showed that ISGylation played an essential role in the downregulation of ΔNp63α. Anticancer drugs, including doxorubicin, induced ΔNp63α ISGylation and caspase-2 activation, leading to cleavage of ISGylated ΔNp63α in the nucleus and subsequent release of its inhibitory domain to the cytoplasm. ISGylation ablated the ability of ΔNp63α to promote anchorageindependent cell growth and tumor formation in vivo as well to suppress the transactivities of proapoptotic p53 family members. These findings establish ISG15 as a tumor suppressor via its conjugation to ΔNp63α and provide a molecular rationale for therapeutic use of doxorubicin against ΔNp63α-mediated cancers.

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“…Because type I IFN are known to induce the ISG15 pathway (22,23,26), a combined use of type I IFN and CPT (or other TOP1-targeting drugs) is expected to increase CPT sensitivity in tumors expressing low levels of ISG15. Indeed, IFN have been shown to exhibit synergistic anticancer activity with CPT-11 against human colon cancer xenografts in nude mice (39,40). It is also interesting to note that all-trans retinoic acid is known to induce ISG15 expression possibly through type I IFN (41).…”

Section: Discussionmentioning

confidence: 99%

ISG15 as a novel tumor biomarker for drug sensitivity

Desai¹,

Wood²,

Tsai³

et al. 2008

Molecular Cancer Therapeutics

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Tumor cells are known to exhibit highly varied sensitivity to camptothecins (CPT; e.g., irinotecan and topotecan). However, the factors that determine CPT sensitivity/ resistance are largely unknown. Recent studies have shown that the ubiquitin-like protein, IFN-stimulated gene 15 (ISG15), which is highly elevated in many human cancers and tumor cell lines, antagonizes the ubiquitin/ proteasome pathway. In the present study, we show that ISG15 is a determinant for CPT sensitivity/resistance possibly through its effect on proteasome-mediated repair of topoisomerase I (TOP1)-DNA covalent complexes. First, short hairpin RNA-mediated knockdown of either ISG15 or UbcH8 (major E2 for ISG15) in breast cancer ZR-75-1 cells decreased CPT sensitivity, suggesting that ISG15 overexpression in tumors could be a factor affecting intrinsic CPT sensitivity in tumor cells. Second, the level of ISG15 was found to be significantly reduced in several tumor cells selected for resistance to CPT, suggesting that altered ISG15 regulation could be a significant determinant for acquired CPT resistance. Parallel to reduced CPT sensitivity, short hairpin RNAmediated knockdown of either ISG15 or UbcH8 in ZR-75-1 cells resulted in increased proteasomal degradation of CPT-induced TOP1-DNA covalent complexes. Taken together, these results suggest that ISG15, which interferes with proteasome-mediated repair of TOP1-DNA covalent complexes, is a potential tumor biomarker for CPT sensitivity.

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Interferon potentiates antiproliferative activity of CPT-11 against human colon cancer xenografts

Cited by 20 publications

References 7 publications

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

Chemosensitivity is controlled by p63 modification with ubiquitin-like protein ISG15

ISG15 as a novel tumor biomarker for drug sensitivity

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