Cell Cycle ; Cell Cycle Proteins ; analysis ; antagonists & inhibitors ; physiology ; Cell Differentiation ; Cell Proliferation ; Humans ; Membrane Proteins ; analysis ; antagonists & inhibitors ; physiology ; Neoplasm Proteins ; analysis ; antagonists & inhibitors ; physiology ; Neoplasms ; enzymology ; therapy ; Protein Tyrosine Phosphatases ; analysis ; antagonists & inhibitors ; physiology

Multidrug resistance (MDR) in cancer cells can significantly attenuate the response to chemotherapy and increase the likelihood of mortality. The major mechanism involved in conferring MDR is the overexpression of ATP-binding cassette (ABC) transporters, which can increase efflux of drugs from cancer cells, thereby decreasing intracellular drug concentration. Modulators of ABC transporters have the potential to augment the efficacy of anticancer drugs. This editorial highlights some major findings related to ABC transporters and current strategies to overcome MDR.
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; antagonists & inhibitors ; metabolism ; ATP-Binding Cassette, Sub-Family B, Member 1 ; antagonists & inhibitors ; metabolism ; Antineoplastic Agents ; therapeutic use ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; Molecular Targeted Therapy ; Multidrug Resistance-Associated Proteins ; antagonists & inhibitors ; metabolism ; Nanomedicine ; Neoplasm Proteins ; antagonists & inhibitors ; metabolism ; Neoplasms ; drug therapy ; metabolism ; Protein-Tyrosine Kinases ; antagonists & inhibitors

OBJECTIVETo explore the effect of antisense oligodeoxynucleotide (ASODN) of survivin gene on apoptosis and chemotherapy sensitivity of lymphoma cell line Raji.

METHODSAnti-survivin phosphorothioate ASODN was synthesized and transfected into Raji cells by lipofectin. MTT assay was used to detect cytotoxicity. Apoptosis was observed by fluorescence microscopy and flow cytometry. Survivin expression was determined by RT-PCR and Western-blotting.

RESULTS(1) survivin ASODN inhibited the cells proliferation in a dose and time dependent manner. (2) A higher apoptosis rate (33.0%) could be induced in Raji cells by survivin ASODN as compared with that induced by the sense oligodeoxynucleotide (11.5%) (P < 0.05). (3) The expression of survivin mRNA and protein significantly decreased after treatment with survivin ASODN. (4) There was a significant increase of cell inhibition rate after exposure to the combination of survivin ASODN and Vm26 as compared to Vm26 or survivin ASODN alone (both P < 0.05).

CONCLUSIONSurvivin ASODN is able to inhibit the proliferation of Raji cells, induce the apoptosis, and enhance the sensitivity of Raji cell to chemotherapy via specific down-regulation of survivin expression.

Apoptosis ; drug effects ; Cell Line, Tumor ; Humans ; Inhibitor of Apoptosis Proteins ; Lymphoma ; drug therapy ; pathology ; Microtubule-Associated Proteins ; antagonists & inhibitors ; genetics ; Neoplasm Proteins ; Oligonucleotides, Antisense ; pharmacology ; Teniposide ; pharmacology

OBJECTIVETo investigate the effects of survivin antisense oligonucleotide (ODN) on cell proliferation and apoptosis of HL-60 cells.

METHODSSynthetic ODN was completely phosphorothioate-modified. Cationic lipid-mediated antisense ODN was transferred into HL-60 cells. The expression of survivin mRNA and protein was detected by RT-PCR and Western Blot. The incorporation of MTT was used as the measurement of HL-60 proliferation. The cell-cycle and apoptosis were analyzed by flow cytometry.

RESULTSHL-60 cells spontaneously expressed survivin mRNA and protein. Both mRNA and protein expression of survivin decreased significantly in the antisense ODN transfected cells in comparison to that in the original cells and cells transfected with sense ODN. Survivin antisense ODN significantly inhibited cell proliferation and induced apoptosis in a dose-dependent manner. The cell-cycle in the antisense ODN-transfected cells stopped at the G2/M phase.

CONCLUSIONSAntisense ODN targeting at survivin mRNA can inhibit HL-60 cell proliferation and induce G2/M stop and apoptosis.

Apoptosis ; drug effects ; Cell Cycle ; drug effects ; Cell Proliferation ; drug effects ; HL-60 Cells ; drug effects ; Humans ; Inhibitor of Apoptosis Proteins ; Microtubule-Associated Proteins ; antagonists & inhibitors ; genetics ; Neoplasm Proteins ; antagonists & inhibitors ; genetics ; Oligonucleotides, Antisense ; pharmacology ; RNA, Messenger ; analysis

BACKGROUNDMultidrug resistance to chemotherapeutic agents is an important clinical problem during the treatment of leukemia. The resistance process is multifactorial. To realize the total factors involved in multidrug resistance, we analyzed the differentially expressed proteins of K562 and K562/ADM cells and we investigated one of the up-regulated proteins (CRKL) using siRNA to determine its role in K562/ADM cells.

METHODSAltered protein expressions between K562/S (K562 ADM-sensitive cell line) and K562/ADM (K562 multidrug resistant cell line induced by adriamycin) were identified by 2D-DIGE coupled with mass spectrometry. Meanwhile, we confirmed the differential expression of CRKL and Stathmin in both K562 and K562/ADM cells by Western blot analysis. Furthermore, we used RNA interference to silence the CRKL gene expression.

RESULTSAmong the 9 differentially expressed proteins, 3 were up-regulated in K562/ADM cells, while 6 were down-regulated in the K562/ADM cells compared with its parent cell line. The expression of CRKL was up-regulated significantly in K562/ADM cells, and it can be decreased by recombinant lentivirus. Moreover, the multidrug resistance of K562/ADM cells was efficiently reversed by silence of CRKL gene expression.

CONCLUSIONSThe data provided the differentially expressed proteins in K562 and its resistant cell line and highlights the power of 2D-DIGE for the discovery of resistance markers in cancer. We found CRKL may be a new protein involved in the multidrug resistance of leukaemia cells.

Adaptor Proteins, Signal Transducing ; analysis ; antagonists & inhibitors ; genetics ; Amino Acid Sequence ; Doxorubicin ; pharmacology ; Drug Resistance, Multiple ; Humans ; K562 Cells ; chemistry ; drug effects ; Molecular Sequence Data ; Neoplasm Proteins ; analysis ; Nuclear Proteins ; analysis ; antagonists & inhibitors ; genetics ; Proteomics ; Stathmin ; analysis

AIMTo determine how SDF-1 alpha/CXCR4 activates nuclear factor-kappa B (NF-kappaB) and promotes oral squamous cell carcinoma (OSCC) invasion.

METHODOLOGYA lentivirus-based knockdown approach was utilized to deplete gene expression. NF-kappaB activation was evaluated by Western blot analysis and electrophoretic mobility shift (EMSA).

RESULTSWe show that the activation of NF-kappaB by CXCR4 occurs through the Carma3/Bcl10/Malt1 (CBM) complex in OSCC. We found that loss of components of the CBM complex in HNSCC can inhibit SDF-1 alpha induced phosphorylation and degradation of IkappaBalpha, while TNF alpha induced IKK activation remains unchanged. Further, we identified a role for novel and atypical, but not classical, PKCs in activating IKK through CXCR4. Importantly, inhibition of the CBM complex leads to a significant decrease in SDF-1 alpha mediated invasion of OSCC.

CONCLUSIONThe CBM complex plays a critical role in CXCR4-induced NF-kappaB activation in OSCC. Targeting molecular components of the NF-kappaB signaling pathway may provide an important therapeutic opportunity in controlling the progression and metastasis of OSCC mediated by SDF-1 alpha.

Adaptor Proteins, Signal Transducing ; antagonists & inhibitors ; physiology ; B-Cell CLL-Lymphoma 10 Protein ; CARD Signaling Adaptor Proteins ; antagonists & inhibitors ; physiology ; Carcinoma, Squamous Cell ; pathology ; Caspase Inhibitors ; Caspases ; physiology ; Cell Line, Tumor ; Chemokine CXCL12 ; antagonists & inhibitors ; physiology ; Enzyme Activation ; drug effects ; Gene Silencing ; Genetic Vectors ; genetics ; Humans ; I-kappa B Kinase ; drug effects ; I-kappa B Proteins ; metabolism ; Isoenzymes ; antagonists & inhibitors ; Lentivirus ; genetics ; Membrane Proteins ; antagonists & inhibitors ; physiology ; Mouth Neoplasms ; pathology ; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein ; NF-KappaB Inhibitor alpha ; NF-kappa B ; antagonists & inhibitors ; physiology ; Neoplasm Invasiveness ; Neoplasm Proteins ; antagonists & inhibitors ; physiology ; Phosphorylation ; Plasmids ; genetics ; Protein Kinase C ; antagonists & inhibitors ; Receptors, CXCR4 ; physiology ; Tumor Necrosis Factor-alpha ; pharmacology

The phosphatidylinositol 3 kinase (PI3K) pathway is frequently altered in cancer, including ovarian cancer (OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin (mTOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective mTOR complex-1 (mTORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual mTORC1/mTORC2, Akt, and PI3K inhibitors. Although it is likely that inhibition of the PI3K/Akt/mTOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and/or phosphatase and tensin homolog (PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3K signaling network, PI3K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3K pathway in OC and provide an up-to-date review of clinical trials of novel PI3K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.
Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Drug Resistance, Neoplasm ; Female ; Humans ; Ovarian Neoplasms ; drug therapy ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; physiology ; Proto-Oncogene Proteins c-akt ; antagonists & inhibitors ; physiology ; Signal Transduction ; drug effects ; TOR Serine-Threonine Kinases ; antagonists & inhibitors ; physiology

Antineoplastic Agents, Immunological ; immunology ; pharmacology ; Cell Line, Tumor ; GPI-Linked Proteins ; antagonists & inhibitors ; immunology ; Humans ; Neoplasm Proteins ; analysis ; immunology ; Pancreatic Neoplasms ; drug therapy ; immunology ; pathology

No abstract available.
Carcinoma, Hepatocellular/enzymology/*metabolism/pathology ; Cell Proliferation/drug effects ; Cyclooxygenase 2 Inhibitors/*pharmacology ; Cyclooxygenase Inhibitors/pharmacology ; Humans ; Liver Neoplasms/enzymology/*metabolism/pathology ; Microtubule-Associated Proteins/*antagonists & inhibitors/metabolism ; Neoplasm Proteins/*antagonists & inhibitors/metabolism ; Nitrobenzenes/pharmacology ; Sulfonamides/pharmacology

Breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2) is an ATP-binding cassette (ABC) transporter identified as a molecular cause of multidrug resistance (MDR) in diverse cancer cells. BCRP physiologically functions as a part of a self-defense mechanism for the organism; it enhances elimination of toxic xenobiotic substances and harmful agents in the gut and biliary tract, as well as through the blood-brain, placental, and possibly blood-testis barriers. BCRP recognizes and transports numerous anticancer drugs including conventional chemotherapeutic and targeted small therapeutic molecules relatively new in clinical use. Thus, BCRP expression in cancer cells directly causes MDR by active efflux of anticancer drugs. Because BCRP is also known to be a stem cell marker, its expression in cancer cells could be a manifestation of metabolic and signaling pathways that confer multiple mechanisms of drug resistance, self-renewal (stemness), and invasiveness (aggressiveness), and thereby impart a poor prognosis. Therefore, blocking BCRP-mediated active efflux may provide a therapeutic benefit for cancers. Delineating the precise molecular mechanisms for BCRP gene expression may lead to identification of a novel molecular target to modulate BCRP-mediated MDR. Current evidence suggests that BCRP gene transcription is regulated by a number of trans-acting elements including hypoxia inducible factor 1α, estrogen receptor, and peroxisome proliferator-activated receptor. Furthermore, alternative promoter usage, demethylation of the BCRP promoter, and histone modification are likely associated with drug-induced BCRP overexpression in cancer cells. Finally, PI3K/AKT signaling may play a critical role in modulating BCRP function under a variety of conditions. These biological events seem involved in a complicated manner. Untangling the events would be an essential first step to developing a method to modulate BCRP function to aid patients with cancer. This review will present a synopsis of the impact of BCRP-mediated MDR in cancer cells, and the molecular mechanisms of acquired MDR currently postulated in a variety of human cancers.
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; antagonists & inhibitors ; metabolism ; physiology ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic ; Humans ; Neoplasm Proteins ; antagonists & inhibitors ; metabolism ; physiology ; Neoplasms ; metabolism ; Neoplastic Stem Cells ; metabolism ; Phosphatidylinositol 3-Kinases ; metabolism ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Proto-Oncogene Proteins c-akt ; metabolism ; Signal Transduction ; Substrate Specificity