Pharmacogenetics of Anticancer Drug Sensitivity in Non-Small Cell Lung Cancer

Danesi, Romano; Braud, Filippo de; Fogli, Stefano; Pas, Tommaso Martino De; Paolo, Antonello Di; Curigliano, Giuseppe; Tacca, M. Del

doi:10.1124/pr.55.1.4

Cited by 66 publications

(54 citation statements)

References 247 publications

(357 reference statements)

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“…Importantly, giant marker and dicentric chromosomes were present in only the Tbx2-expressing cells. Interestingly, small marker chromosomes have been shown to be useful to cancer cells because they can harbor extra copies of genes that make a cell resistant to drugs used in chemotherapy (Danesi et al, 2003). The increased number of these chromosomes in CT-Tbx2 cells may explain why, although grossly abnormal, these cells are still capable of dividing and give rise to cells that are resistant to the chemotherapeutic drug cisplatin.…”

Section: Discussionmentioning

confidence: 99%

Ectopic Tbx2 expression results in polyploidy and cisplatin resistance

et al. 2007

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Section: Discussionmentioning

confidence: 99%

Ectopic Tbx2 expression results in polyploidy and cisplatin resistance

et al. 2007

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“…To evaluate the expression of the dCK, a rate-limiting enzyme required for the activation of the pyrimidine analogue gemcitabine, and of the cytosolic 5 0 -NT, responsible for deactivation of nucleotides and of the activated gemcitabine (Danesi et al, 2003), MIAPaCa-2 cells were treated with fluvastatin (1 and 5 mM) or vehicle alone for 72 h. Quantitative real-time PCR analysis was performed as described previously (Giovannetti et al, 2005). Briefly, RNA (1 mg) was reverse transcribed at 371C for 1 h in a 100-ml reaction volume containing 0.8 mM deoxynucleotide mix (dNTPs), 200 U of Moloney murine leukaemia virus reverse transcriptase (MMLV-RT), 40 U of RNase inhibitor and 0.05 mg ml À1 random primers.…”

Section: Assessement Of Synergism or Antagonismmentioning

confidence: 99%

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

et al. 2005

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The new combination between the nucleoside analogue gemcitabine and the cholesterol-lowering drug fluvastatin was investigated in vitro and in vivo on the human pancreatic tumour cell line MIAPaCa-2. The present study demonstrates that fluvastatin inhibits proliferation, induces apoptosis in pancreatic cancer cells harbouring a p21ras mutation at codon 12 and synergistically potentiates the cytotoxic effect of gemcitabine. The pharmacologic activities of fluvastatin are prevented by administration of mevalonic acid, suggesting that the shown inhibition of geranyl-geranylation and farnesylation of cellular proteins, including p21rhoA and p21ras, plays a major role in its anticancer effect. Fluvastatin treatment also indirectly inhibits the phosphorylation of p42ERK2/mitogen-activated protein kinase, the cellular effector of ras and other signal transduction peptides. Moreover, fluvastatin administration significantly increases the expression of the deoxycytidine kinase, the enzyme required for the activation of gemcitabine, and simultaneously reduces the 5 0 -nucleotidase, responsible for deactivation of gemcitabine, suggesting a possible additional role of these enzymes in the enhanced cytotoxic activity of gemcitabine. Finally, a significant in vivo antitumour effect on MIAPaCa-2 xenografts was observed with the simultaneous combination of fluvastatin and gemcitabine, resulting in an almost complete suppression and a marked delay in relapse of tumour growth. In conclusion, the combination of fluvastatin and gemcitabine is an effective cytotoxic, proapoptotic treatment in vitro and in vivo against MIAPaCa-2 cells by a mechanism of action mediated, at least in part, by the inhibition of p21ras and rhoA prenylation. The obtained experimental findings might constitute the basis for a novel translational research in humans.

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“…Chemotherapy has a role either as strategic treatment for locally advanced disease or as a palliative treatment for metastatic tumors. 1,2 However, clinical use of chemotherapy is still unsatisfactory due to limited response rate, small survival benefit and poor prognosis. Therefore, the development of novel anticancer drug, which is more effective and shows less side effect for cancer patients, is urgently needed.…”

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confidence: 99%

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

Huang

Hsu

Chen

et al. 2011

Intl Journal of Cancer

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Drugs in clinical use with indole structure exhibit side effects. Therefore, to search for indole compounds with more efficacy and less side effect for cancer therapy, we developed a novel indole compound SK228 and examined its effects and mechanisms on antitumor growth and invasion inhibition in cell and tumor xenografts in nude mice models. SK228 significantly inhibited growth of different lung and esophageal cancer cell lines at sub-micromolar range, but not normal lung cells. SK228 induced DNA damages mainly by producing reactive oxygen species (ROS) resulting in apoptosis. SK228 treatment increased the release of cytochrome c into the cytosol along with the increased activity of caspase-3 and -9 without affecting caspase-8, whereas these effects were attenuated by ROS inhibitor. The expression levels of BCL-2 family regulators were also affected. Moreover, low-dose SK228 significantly reduced the invasion of cancer cells. The active phosphorylated form of FAK/Paxillin signaling pathway proteins and active form of RhoA were decreased. Moreover, the F-actin cytoskeleton was disrupted after low-dose SK228 treatment. Growth of an A549 tumor cell xenograft was markedly inhibited without significant side effects. SK228-induced apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry of cleaved caspase-3 in tumors from treated mice. Our study provides the first evidence that SK228 exhibits cancer cell-specific cytotoxicity by inducing mitochondria-mediated apoptosis. In addition, SK228 inhibits cancer cell invasion via FAK/Paxillin disruption at noncytotoxic doses. SK228 can be further tested as a pharmaceutical compound for cancer treatment.There are three standard therapies for cancer treatment including surgery, radiotherapy and chemotherapy. Chemotherapy has a role either as strategic treatment for locally advanced disease or as a palliative treatment for metastatic tumors. 1,2 However, clinical use of chemotherapy is still unsatisfactory due to limited response rate, small survival benefit and poor prognosis. Therefore, the development of novel anticancer drug, which is more effective and shows less side effect for cancer patients, is urgently needed.Several studies have indicated that compounds containing indole structure are highly cytotoxic against many tumoral cell lines, and the indole ring seems to be the core nucleus of several potent tubulin polymerization inhibitors. 3 The most wildly used clinical antimicrotubule drugs containing indole structure is Vinca alkaloids. They are also known as microtubule-destabilizing agents, which includes natural compound vinblastine, vincristine and two semisynthetic derivatives, vindesine and vinorelbine. 4 Several new compounds containing indole structure isolated from natural sources or synthesized were shown to have high potential for cancer treatment. For example, indole-3-carbinol (I3C) was isolated from cruciferous vegetables with high potential for cancer therapy. I3C and its metabolites inhibited ...

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Pharmacogenetics of Anticancer Drug Sensitivity in Non-Small Cell Lung Cancer

Cited by 66 publications

References 247 publications

Ectopic Tbx2 expression results in polyploidy and cisplatin resistance

Ectopic Tbx2 expression results in polyploidy and cisplatin resistance

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

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