Progress in treatment of small-cell lung cancer: role of CPT-11

Saijo, Nagahiro

doi:10.1038/sj.bjc.6601456

Cited by 18 publications

(6 citation statements)

References 34 publications

(17 reference statements)

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“…Anti-metabolite agents characterized by 5-fluorouracil (5-FU), 6-mercaptopurine, and methotrexate induce genotoxic stress during S phase [ 219 , 220 ]. Topoisomerase inhibitors such as irinotecan (CPT-11) and etoposide (VP-16) interrupts the separation of DNA strands during DNA replication and transcription [ 221 , 222 ]. However, these drugs show anti-tumor effects only when cancer cells are under proliferative conditions.…”

Section: The Disruption Of Degradation Pathway Of C-myc In Cancer Celmentioning

confidence: 99%

Emerging roles of Myc in stem cell biology and novel tumor therapies

Yoshida

2018

J Exp Clin Cancer Res

183

153

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The pathophysiological roles and the therapeutic potentials of Myc family are reviewed in this article. The physiological functions and molecular machineries in stem cells, including embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, are clearly described. The c-Myc/Max complex inhibits the ectopic differentiation of both types of artificial stem cells. Whereas c-Myc plays a fundamental role as a “double-edged sword” promoting both iPS cells generation and malignant transformation, L-Myc contributes to the nuclear reprogramming with the significant down-regulation of differentiation-associated genetic expression. Furthermore, given the therapeutic resistance of neuroendocrine tumors such as small-cell lung cancer and neuroblastoma, the roles of N-Myc in difficult-to-treat tumors are discussed. N-Myc-driven neuroendocrine tumors tend to highly express NEUROD1, thereby leading to the enhanced metastatic potential. Importantly enough, accumulating evidence strongly suggests that c-Myc can be a promising therapeutic target molecule among Myc family in terms of the biological characteristics of cancer stem-like cells (CSCs). The presence of CSCs leads to the intra-tumoral heterogeneity, which is mainly responsible for the therapeutic resistance. Mechanistically, it has been shown that Myc-induced epigenetic reprogramming enhances the CSC phenotypes. In this review article, the author describes two major therapeutic strategies of CSCs by targeting c-Myc; Firstly, Myc-dependent metabolic reprogramming is closely related to CD44 variant-dependent redox stress regulation in CSCs. It has been shown that c-Myc increases NADPH production via enhanced glutaminolysis with a finely-regulated mechanism. Secondly, the dormancy of CSCs due to FBW7-depedent c-Myc degradation pathway is also responsible for the therapeutic resistance to the conventional anti-tumor agents, the action points of which are largely dependent on the operation of the cell cycle. That is why the loss-of-functional mutations of FBW7 gene are expected to trigger “awakening” of dormant CSCs in the niche with c-Myc up-regulation. Collectively, although the further research is warranted to develop the effective anti-tumor therapeutic strategy targeting Myc family, we cancer researchers should always catch up with the current advances in the complex functions of Myc family in highly-malignant and heterogeneous tumor cells to realize the precision medicine.

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Section: The Disruption Of Degradation Pathway Of C-myc In Cancer Celmentioning

confidence: 99%

Emerging roles of Myc in stem cell biology and novel tumor therapies

Yoshida

2018

J Exp Clin Cancer Res

183

153

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“…1,2 Although up to 90% of SCLC tumors initially respond to chemotherapy, patients with SCLC often relapse with multidrug resistant state. There are several types of multidrug resistance (MDR) to anticancer agents, and some of them were identified in human carcinoma cell lines in vitro.…”

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confidence: 99%

Doxorubicin induces expression of multidrug resistance-associated protein 1 in human small cell lung cancer cell lines by the c-jun N-terminal kinase pathway

et al. 2005

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Multidrug resistance (MDR) is a major impediment to successful chemotherapy for lung cancer. Overexpression of multidrug resistance-associated protein 1 (MRP1) appears to be involved in MDR development in lung cancer cells. A number of chemotherapeutic agents including doxorubicin (DOX) were reported to induce MRP1 expression in human lung cancer cells. In our study, we investigated the mechanism by which DOX induces MRP1 expression in human small cell lung cancer (SCLC) cell lines, GLC4 and NCI-H82. These cells expressed MRP1 protein at low levels and were sensitive to DOX. Doxorubicin at 50 nM induced a marked increase in MRP1 expression in 24 hr, and stimulated c-jun N-terminal kinase (JNK) activity. Treatment with a JNK inhibitor, SP600125, significantly inhibited MRP1 induction. Furthermore, transfection with JNK1 and JNK2 antisense oligonucleotides markedly inhibited DOX-induced MRP1 expression. Chromatin immunoprecipitation assays revealed an enhanced recruitment of phosphorylated c-jun to the MRP1 promoter containing the AP-1 site upon DOX stimulation, which was inhibited by pretreatment with SP600125. Surprisingly, GLC4 cells exposed to DOX for 24 hr maintained increased MRP1 expression and resistance to DOX for at least 3 weeks. Pretreatment with SP600125 before DOX stimulation blocked the appearance of the MDR phenotype as well as MRP1 induction in GLC4 cells. These findings suggest that JNK activation may play an essential role for the induction of MRP1 protein in human SCLC cells by chemotherapeutic agents and that combined treatment of a JNK inhibitor with anticancer drugs may prevent the development of MDR by the abrogation of MRP1 induction. ' 2005 Wiley-Liss, Inc.Key words: MRP1; JNK; doxorubicin; small-cell lung cancer; multidrug resistance Small cell lung cancer (SCLC) accounts for 15-25% of all lung cancer patients.1,2 Although up to 90% of SCLC tumors initially respond to chemotherapy, patients with SCLC often relapse with multidrug resistant state. There are several types of multidrug resistance (MDR) to anticancer agents, and some of them were identified in human carcinoma cell lines in vitro. One of the mechanisms of MDR is decreased accumulation of drug within cells because of reduced inward transport or increased drug efflux, such as overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. 3 P-glycoprotein (P-gp) that was cloned from KB-C 2.5 cells was the first ABC transporter identified. 4 Overexpression of P-gp has been detected in many multidrug resistant tumor cell lines and a variety of tumors from patients with both acquired and inherent drug resistance.5 Although P-gp is implicated in drug resistance in a number of tumor types, it is infrequently expressed in lung cancer cells. Another ABC transporter was cloned from the doxorubicin (DOX) resistant H69/AR SCLC cell line by Cole et al. 6 The transporter was designated as multidrug resistance-associated protein 1 (MRP1). The MRP family is now composed of 9 related ABC transporters that are able to transp...

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“…In our case, because of the history of ischemic heart disease and poor cardiopulmonary function, adriamycin, cyclophosphamide or bleomycin was avoided and combination chemotherapy of divided administration of cisplatin and irinotecan hydrochloride was selected. Considering the poor renal function, the dose of irinotecan hydrochloride was reduced compared to the usual dosage for lung cancer treatment [12], which would possibly cause a relatively short period of remission.…”

Section: Discussionmentioning

confidence: 99%