Recent Advances on the Molecular Mechanisms Involved in the Drug Resistance of Cancer Cells and Novel Targeting Therapies

Mimeault, Murielle; Hauke, Ralph J.; Karmakar, Saswati

doi:10.1038/sj.clpt.6100296

Cited by 156 publications

(160 citation statements)

References 227 publications

(515 reference statements)

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“…[47][48][49][50] Therefore, it is imperative to identify the mechanisms responsible for the survival and maintenance of CSC in order to design new therapeutic strategies targeting CSCs. Importantly, the non-CSCs display certain degree of plasticity to spontaneously dedifferentiate into CSC phenotype.…”

Section: Discussionmentioning

confidence: 99%

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Sastry

Al-Muftah

et al. 2014

Cell Death Differ

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Emerging evidence suggests that the resistance of cancer stem cells (CSC) to many conventional therapies is one of the major limiting factors of cancer therapy efficacy. Identification of mechanisms responsible for survival and self-renewal of CSC will help design new therapeutic strategies that target and eliminate both differentiated cancer cells and CSC. Here we demonstrated the potential role of proapoptotic protein BAD in the biology of CSC in melanoma, prostate and breast cancers. We enriched CD44 þ /CD24 À cells (CSC) by tumorosphere formation and purified this population by FACS. Both spheres and CSC exhibited increased potential for proliferation, migration, invasion, sphere formation, anchorage-independent growth, as well as upregulation of several stem cell-associated markers. We showed that the phosphorylation of BAD is essential for the survival of CSC. Conversely, ectopic expression of a phosphorylation-deficient mutant BAD induced apoptosis in CSC. This effect was enhanced by treatment with a BH3-mimetic, ABT-737. Both pharmacological agents that inhibit survival kinases and growth factors that are involved in drug resistance delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. Furthermore, the frequency and self-renewal capacity of CSC was significantly reduced by knocking down the BAD expression. Consistent with our in vitro results, significant phosphorylation of BAD was found in CD44 þ CSC of 83% breast tumor specimens. In addition, we also identified a positive correlation between BAD expression and disease stage in prostate cancer, suggesting a role of BAD in tumor advancement. Our studies unveil the role of BAD in the survival and self-renewal of CSC and propose BAD not only as an attractive target for cancer therapy but also as a marker of tumor progression.

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Section: Discussionmentioning

confidence: 99%

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Sastry

Al-Muftah

et al. 2014

Cell Death Differ

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“…Alternatively, enhanced expression and/or activity of enzymes involved in the metabolism of ceramide, including SphK1 that produces the antiapoptotic S1P sphingolipid and decreases ceramide levels, contributes to intrinsic or acquired drug resistance of cancer cells (24,25). Targeting the sphingolipid metabolism for improving tumor chemosensitivity has therefore emerged as a novel therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug

Guillermet-Guibert

Davenne

Pchejetski

et al. 2009

Molecular Cancer Therapeutics

116

101

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Defeating pancreatic cancer resistance to the chemotherapeutic drug gemcitabine remains a challenge to treat this deadly cancer. Targeting the sphingolipid metabolism for improving tumor chemosensitivity has recently emerged as a promising strategy. The fine balance between intracellular levels of the prosurvival sphingosine-1-phosphate (S1P) and the proapoptotic ceramide sphingolipids determines cell fate. Among enzymes that control this metabolism, sphingosine kinase-1 (SphK1), a tumor-associated protein overexpressed in many cancers, favors survival through S1P production, and inhibitors of SphK1 are used in ongoing clinical trials to sensitize epithelial ovarian and prostate cancer cells to various chemotherapeutic drugs. We here report that the cellular ceramide/S1P ratio is a critical biosensor for predicting pancreatic cancer cell sensitivity to gemcitabine. A low level of the ceramide/S1P ratio, associated with a high SphK1 activity, correlates with a robust intrinsic pancreatic cancer cell chemoresistance toward gemcitabine. Strikingly, increasing the ceramide/S1P ratio, by using pharmacologic (SphK1 inhibitor or ceramide analogue) or small interfering RNA-based approaches to up-regulate intracellular ceramide levels or reduce SphK1 activity, sensitized pancreatic cancer cells to gemcitabine. Conversely, decreasing the ceramide/ S1P ratio, by up-regulating SphK1 activity, promoted gemcitabine resistance in these cells. Development of novel pharmacologic strategies targeting the sphingolipid metabolism might therefore represent an interesting promising approach, when combined with gemcitabine, to defeat pancreatic cancer chemoresistance to this drug.

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“…However, its efficacy is often limited by the development of MDR, which has been linked to the up-regulation of P-glycoprotein (P-gp) in cancer cells. 1 It is known that tumor progression often is accompanied by increased COX-2 expression, and selective COX-2 inhibitors prevent the formation of multiple tumor types in experimental animals. 2 In fact, it is also known that MDR caused by multidrug resistance associated protein 1 (MRP-1) is modulated by nonsteroidal antiinflammatory drugs (NSAIDs), nonselective COX inhibitors such as indomethacin 1a, or COX-2 selective inhibitors.…”

mentioning

confidence: 99%

Indomethacin Analogues that Enhance Doxorubicin Cytotoxicity in Multidrug Resistant Cells without Cox Inhibitory Activity

Arisawa

Kasaya

Obata

et al. 2011

ACS Med. Chem. Lett.

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b S Supporting Information M ultidrug resistance (MDR) continues to be a serious problem in cancer therapy and is one of the limiting factors in the development and application of antitumor drugs. Doxorubicin is a chemotherapeutic drug widely used for the treatment of various solid tumors. However, its efficacy is often limited by the development of MDR, which has been linked to the up-regulation of P-glycoprotein (P-gp) in cancer cells.1 It is known that tumor progression often is accompanied by increased COX-2 expression, and selective COX-2 inhibitors prevent the formation of multiple tumor types in experimental animals.2 In fact, it is also known that MDR caused by multidrug resistance associated protein 1 (MRP-1) is modulated by nonsteroidal antiinflammatory drugs (NSAIDs), nonselective COX inhibitors such as indomethacin 1a, or COX-2 selective inhibitors. 3,4 Mazzanti reported that the MDR phenotype might be associated with the expression of COX-2 in a human hepatocellular carcinoma cell line.5 Cho showed a mechanism by which COX inhibitors exerted an enhancing effect on the cytotoxic effect of doxorubicin via direct inhibition of P-gpATPase activity in human esophageal squamous cell carcinoma cell lines.6 However, it is less certain whether COX-1 and/or COX-2 activity is directly related to the MDR property of cancer cells. Indomethacin (1a, Figure 1) is a clinically useful NSAID with an indole structure, which inhibits both COX-1 and COX-2. In indomethacin, the two stable forms, the s-trans form and the s-cis form, around the amide bond are known (Figure 1). The COX inhibitory activities are closely related to the conformation of indomethacin itself. It has been reported that the bioactive conformations of indomethacin in complexes with COX-1 and COX-2 are the s-trans form 7 and the s-cis form, 8 respectively (4COX.pdb and 1PGG.pdb). We thought that the introduction of an alkyl substituent other than a methyl group at the 2-position of indomethacin might restrict its conformation in the s-cis or s-trans form, respectively, due to steric repulsion or πÀπ stacking interaction by the introduced substituent with the N-4-chlorobenzoyl side chain. When the substituent at the 2-position (R) is an alkyl group bulkier than methyl, the s-cis form can be more stable than the s-trans form due to steric repulsion. However, introduction of a phenyl substituent at the 2-position may make the s-trans form more stable due to πÀπ stacking (Figure 2). That these conformationally restricted analogues may be selectively active toward COX-1 or COX-2 offers some insight into the relationship between the COX-1 and/or COX-2 inhibitory effect and the MDR property of cancer cells. Since we have just developed a novel synthetic method for various substituted indoles using a combination of isomerization and enamide-ene metathesis, 9,10 consequently we decided to design and synthesize the indomethacin analogues 1bÀd substituted at the 2-position. 11The present study was carried out to investigate whether the COX activity of a series ...

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Recent Advances on the Molecular Mechanisms Involved in the Drug Resistance of Cancer Cells and Novel Targeting Therapies

Cited by 156 publications

References 227 publications

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug

Indomethacin Analogues that Enhance Doxorubicin Cytotoxicity in Multidrug Resistant Cells without Cox Inhibitory Activity

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