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PubMed2003

Anticancer drug resistance induced by disruption of the Saccharomyces cerevisiae NPR2 gene: a novel component involved in cisplatin- and doxorubicin-provoked cell kill.

The therapeutic potential of antitumor drugs is seriously limited by the manifestation of cellular drug resistance. We used the budding yeast Saccharomyces cerevisiae as a model system to identify novel mechanisms of resistance to one of the most active anticancer agents, cisplatin. We pinpointed NPR2 (nitrogen permease regulator 2) as a gene whose disruption conferred resistance to cisplatin. In addition, we observed a 4-fold cross-resistance of yeast npr2Delta cells (i.e., cells from which the NPR2 gene had been disrupted) to the anticancer drug doxorubicin, in combination with hypersensitivity to cadmium chloride. Furthermore, npr2Delta cells displayed unaltered cellular cisplatin and doxorubicin accumulation and showed an enhanced rate of spontaneous mutation compared with the isogenic parent. These data indicate that the npr2Delta phenotype overlaps that of the sky1Delta cells that we characterized previously (Mol Pharmacol 61:659-666, 2002). Therefore, we generated yeast npr2Delta sky1Delta double-knockout cells and performed clonogenic survival assays for cisplatin and doxorubicin, which revealed that NPR2 and SKY1 (SR-protein-specific kinase from budding yeast) are epistatic. The double-knockout strain was just as resistant to cisplatin and doxorubicin as the single-knockout strain that was most resistant to either drug. In conclusion, we identified NPR2 as a novel component involved in cell kill provoked by cisplatin and doxorubicin, and our data support the hypothesis that NPR2 and SKY1 may use mutual regulatory routes to mediate the cytotoxicity of these anticancer drugs.

Antineoplastic Agents↗

PubMed2004

Overexpression of a dominant-negative mutant Ubc9 is associated with increased sensitivity to anticancer drugs.

Ubc9 is an E2-conjugating enzyme required for sumoylation and has been implicated in regulating several critical cellular pathways. We have shown previously that Ubc9 is important for sumoylation and nucleolar delocalization of topoisomerase (topo) I in response to topo I inhibitors such as topotecan. However, the role for Ubc9 in tumor drug responsiveness is not clear. In this study, we found that although MCF7 cells expressing a Ubc9 dominant-negative mutant (Ubc9-DN) display decreased activity of topo I, these cells are more sensitive to the topo I inhibitor topotecan and other anticancer agents such as VM-26 and cisplatin. In addition, we found that alteration of Ubc9 expression correlates with drug responsiveness in tumor cell lines. To understand possible mechanisms of Ubc9-associated drug responsiveness, we examined several proteins that have been shown to interact with Ubc9 and that may be involved in drug responsiveness. One such protein is Daxx, which is a Fas-associated protein that plays a role in Fas-mediated apoptosis by participating in a caspase-independent pathway through activation of apoptosis signal-regulating kinase 1 and c-Jun NH(2)-terminal kinase. We found that cells expressing Ubc9-DN accumulate more cytoplasmic Daxx than the control cells. Because cytoplasmic Daxx is believed to participate in cellular apoptosis, we suggest that the interaction of Ubc9 with Daxx and subsequent alteration in the subcellular localization of Daxx may contribute to the increased sensitivity to anticancer drugs in the cells expressing Ubc9-DN. Finally, we found that overexpression of Daxx sensitizes cells to anticancer drugs possibly in part through alterations of the ratio of cytoplasmic and nuclear Daxx. Together, our results suggest a role for Ubc9 in tumor drug responsiveness.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Expression of toll-like receptor 4 on dendritic cells is significant for anticancer effect of dendritic cell-based immunotherapy in combination with an active component of OK-432, a streptococcal preparation.

A lipoteichoic acid-related molecule OK-PSA is an active component of OK-432, a Streptococcus-derived anticancer immunotherapeutic agent. In the present study, we first examined the effect of OK-PSA on the maturation of dendritic cells (DCs) in vitro by using the DCs derived from 5 healthy donors and 10 patients with head and neck cancer with or without expression of toll-like receptor 4 (TLR4) or MD-2 mRNA. OK-PSA treatment effectively increased the surface expression of MHC class II, CD80, CD83, and CD86. OK-PSA-stimulated DCs secreted the cytokines that can induce helper T-cell 1 (Th1)-type T-cell response, and stimulated allogeneic T cells to produce IFN-gamma and to elicit an allogeneic antigen-specific cytotoxicity. These activities almost depended on expression of TLR4 and MD-2 genes. We next investigated the in vivo anticancer effect of intratumoral administration of syngeneic DCs followed by OK-PSA against established tumors in mice. C57BL/6 mice, which express wild-type TLR4, and C57BL/6-derived TLR4-knockout (TLR4(-/-)) mice were used. Although OK-PSA accelerated the antitumor effect of intratumoral DC administration in wild-type mice bearing syngeneic tumors, the antitumor effect of OK-PSA as well as of the combination therapy with DCs and OK-PSA was not significant in TLR4(-/-) mice. Interestingly, an administration of wild-type-mouse-derived DCs followed by OK-PSA exhibited a marked antitumor effect even in the TLR4(-/-) mice. These findings suggest that OK-PSA may be a potent adjuvant for local DC therapy, and that DC therapy followed by OK-PSA is able to elicit anticancer activity even in a TLR4-deficient host when TLR4 is expressed only in DCs injected intratumorally.

Adjuvants, Immunologic↗

PubMed2005

Anticancer activity of the antibiotic clioquinol.

Clioquinol, a metal chelator, has been used for many years as an antimicrobial agent and more recently as a potential treatment for Alzheimer's disease. Because it binds copper and zinc, metals essential for the activity of the enzyme superoxide dismutase-1 (SOD1), a potential target for anticancer drug development, we investigated its effects on human cancer cells. Treatment with clioquinol reduced the viability of eight different human cancer cell lines in a concentration-dependent manner, with IC(50) values in the low micromolar range. Biochemical analysis revealed that clioquinol induced cancer cell death through apoptotic pathways that require caspase activity. Although clioquinol induced modest inhibition of SOD1 activity in treated cells, comparable inhibition by a known SOD1 inhibitor, diethyldithiocarbamate, did not result in cytotoxicity. The addition of copper, iron, or zinc did not rescue cells from cliquinol-induced cytotoxicity but enhanced its killing, arguing against metal chelation as its major mechanism of action. To test if clioquinol might act as an ionophore, a fluorescent probe was used to monitor intracellular zinc concentrations. The addition of clioquinol resulted in elevated levels of intracellular zinc, indicating that clioquinol acts as a zinc ionophore. In an in vivo xenografts mouse model, clioquinol inhibited tumor growth of xenografts over a 6-week period, without inducing visible toxicity. Our results show that clioquinol has anticancer effects both in vitro and in vivo. Transition metal ionophores may be a subclass of metal chelators with anticancer activity deserving of further development.

Animals↗

PubMed2005

A potential synergistic anticancer effect of paclitaxel and amifostine on endometrial cancer.

Although paclitaxel is one of the most effective chemotherapeutic agents, its usefulness is still limited in advanced and recurrent endometrial cancer. Amifostine protection of normal tissues against the side effects of chemotherapeutic agents has been clinically proven in cancer patients; however, its application in endometrial cancer has not been fully evaluated. We have investigated the use of paclitaxel and amifostine in controlling the growth of poorly differentiated endometrial cancer cells, Hec50co, in vitro and in vivo. Our studies show that amifostine had direct anticancer effects on endometrial cancer cells in vitro by arresting the cell cycle at the G1 phase and inducing apoptosis. Amifostine also inhibited s.c. tumor growth in athymic mice. Paclitaxel IC50 value was reduced from 14 to 2 nmol/L with pretreatment of a single dose of 178 micromol/L of amifostine for 72 hours. Amifostine also synergized with paclitaxel in the arrest of the cell cycle at the G2-M phase and in the induction of apoptosis. This two-drug regimen inhibited s.c. tumor growth as well as improved mouse survival significantly more than paclitaxel alone. Amifostine also significantly improved paclitaxel-induced cytotoxic effects on peripheral blood profiles. Our studies show that amifostine has direct anticancer effects on endometrial cancer. Our data have also shown a potential anticancer synergy between amifostine and paclitaxel in vitro and in vivo, whereas amifostine maintained a protective role in peripheral blood profiles. The dual specificity of amifostine action should be further investigated.

Amifostine↗

PubMed2005

Novel extracellular vesicles mediate an ABCG2-dependent anticancer drug sequestration and resistance.

Overexpression of the multidrug efflux transporter ABCG2 in the plasma membrane of cancer cells confers resistance to various anticancer drugs, including mitoxantrone. Here, we explored the mechanism underlying drug resistance in the MCF-7 breast cancer sublines MCF-7/MR and MCF-7/FLV1000 cells in which wild-type (R482) ABCG2 overexpression is highly confined to cell-cell attachment zones. The latter comprised the membrane of novel extracellular vesicles in which mitoxantrone was rapidly and dramatically sequestered. After 12 hours of incubation with mitoxantrone, the estimated intravesicular drug concentration was approximately 1,000-fold higher than in the culture medium. This drug compartmentalization was prevented by the specific and potent ABCG2 transport inhibitors Ko143 and fumitremorgin C, thereby resulting in restoration of drug sensitivity. Consistently, this intravesicular drug concentration was abrogated by energy deprivation and was restored upon provision of energy substrates. Fine-structure studies corroborated the presence of numerous large extracellular vesicles that were highly confined to cell-cell attachment zones between neighbor cells. Furthermore, high-resolution electron microscopy revealed that the membrane of these extracellular vesicles contained microvilli-like invaginations protruding into the intravesicular lumen. It is likely that these microvilli-like projections increase the vesicular membrane surface, thereby allowing for a more efficient ABCG2-dependent intravesicular anticancer drug concentration. Hence, these novel extracellular vesicles mediate the ABCG2-dependent extraction of intracellular drug, thereby serving as cytotoxic drug disposal chambers shared by multiple neighbor cancer cells. This constitutes a novel modality of anticancer drug resistance.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2006

The penetration of anticancer drugs through tumor tissue as a function of cellular adhesion and packing density of tumor cells.

To reach cancer cells in optimal quantities, therapeutic agents must be delivered to tumors through their imperfect blood vascular system, cross vessel walls into the interstitium, and penetrate multiple layers of tissue. Strategies to enhance drug penetration have potential to improve therapeutic outcome. The development of multicellular layers (MCLs), in which tumor cells are grown on a semipermeable Teflon support membrane, has facilitated quantification of drug penetration through solid tissue. The goals of the present study were to quantify the penetration of anticancer drugs as a function of cellular adhesion and packing density and to determine the effects of variable penetration on therapeutic efficacy in this model system. We compared the properties of MCLs grown from two epithelioid and round subclones of a colon carcinoma cell line. One pair of epithelioid and round sublines differed in expression of alpha-E-catenin, and both pairs generated MCLs with different packing density. The penetration of commonly used anticancer agents (paclitaxel, doxorubicin, methotrexate, and 5-fluorouracil) through MCLs derived from these cell lines was significantly greater through the round (loosely packed) than through the epithelioid (tightly packed) sublines. In MCLs treated with doxorubicin, we observed greater survival in the tightly packed cell lines than in the loosely packed cell lines. Impaired penetration of anticancer agents through MCLs derived from the tightly packed cell lines and relative resistance to killing of cells within them by doxorubicin treatment strengthen the role of tumor cell adhesion and packing density as contributing to drug resistance.

Antineoplastic Agents↗

PubMed2006

Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Galpha/Gbetagamma protein complex.

A large number of hormones and local agonists activating guanine-binding protein-coupled receptors (GPCR) play a major role in cancer progression. Here, we characterize the new imidazo-pyrazine derivative BIM-46174, which acts as a selective inhibitor of heterotrimeric G-protein complex. BIM-46174 prevents the heterotrimeric G-protein signaling linked to several GPCRs mediating (a) cyclic AMP generation (Galphas), (b) calcium release (Galphaq), and (c) cancer cell invasion by Wnt-2 frizzled receptors and high-affinity neurotensin receptors (Galphao/i and Galphaq). BIM-46174 inhibits the growth of a large panel of human cancer cell lines, including anticancer drug-resistant cells. Exposure of cancer cells to BIM-46174 leads to caspase-3-dependent apoptosis and poly(ADP-ribose) polymerase cleavage. National Cancer Institute COMPARE analysis for BIM-46174 supports its novel pharmacologic profile compared with 12,000 anticancer agents. The growth rate of human tumor xenografts in athymic mice is significantly reduced after administration of BIM-46174 combined with either cisplatin, farnesyltransferase inhibitor, or topoisomerase inhibitors. Our data validate the feasibility of targeting heterotrimeric G-protein functions downstream the GPCRs to improve anticancer chemotherapy.

Animals↗

PubMed2005

Sulindac enhances the proteasome inhibitor bortezomib-mediated oxidative stress and anticancer activity.

PURPOSE: The nonsteroidal antiinflammatory drug sulindac is a promising chemopreventive agent against colon cancer. Here, we address whether sulindac enhances the anticancer effects of the proteasome inhibitor bortezomib (PS-341) in colon cancer cells. EXPERIMENTAL DESIGN: The synergistic effects of sulindac with bortezomib were evaluated by cell death, colony formation assay, DNA fragmentation, and tumor progression of DLD-1 xenografts. Reactive oxygen species (ROS) generation was detected using carboxy-H2DCFDA or dihydroethidium. Oxidative stress was evaluated by heme oxygenase-1 induction and stress-activated mitogen-activated protein kinases p38 and c-Jun-NH2-kinase phosphorylation. Oxidative DNA damage was evaluated by histone H2AX phosphorylation and accumulation of 8-hydroxy-2'-deoxyguanosine. RESULTS: Sulindac and its metabolites enhanced the anticancer effects of bortezomib in DLD-1 and BM314 colon cancer cells. Sulindac induced ROS generation and enhanced bortezomib-mediated oxidative stress and subsequent DNA damage. Their combined effects were highly sensitive to free radical scavengers L-N-acetylcysteine and alpha-tocopherol, but were much less sensitive to a p38 inhibitor SB203580. CONCLUSION: Sulindac synergistically augments the anticancer effects of bortezomib primarily through cooperative ROS generation and oxidative DNA damage, thereby representing a novel combination therapy against colon cancer.

Animals↗

PubMed2004

Tumor necrosis factor-related apoptosis-inducing ligand cooperates with anticancer drugs to overcome chemoresistance in antiapoptotic Bcl-2 family members expressing jurkat cells.

PURPOSE: Overexpression of antiapoptotic Bcl-2 family members has recently been related to resistance to chemo/radiotherapy in several human malignancies, particularly lymphomas. Hence, innovative approaches bypassing this resistance mechanism are required in the therapeutic approach. This study evaluated whether chemoresistance associated with Bcl-2 and Bcl-x(L) overexpression would be overcome by activating the death receptor pathway by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the Jurkat cell model EXPERIMENTAL DESIGN: We made use of genetically modified Jurkat cells to evaluate the effect of Bcl-2 or Bcl-x(L) overexpression on the cytotoxic effect produced by the anticancer drugs doxorubicin, etoposide, and oxaliplatin and TRAIL. Caspase activation was detected by cleavage of caspase-8 and -3. The mitochondrial transmambrane potential was assessed by staining with DiOC(6) and flow cytometry. Caspase activity was blocked by the broad-spectrum caspase inhibitor zVAD-fmk. RESULTS: Bcl-2 and Bcl-x(L) overexpression but not lack of caspase-8 protects the Jurkat cells from the anticancer drug-induced cytolysis. However, Bcl-2/Bcl-x(L) Jurkat cells retained some susceptibility to TRAIL-induced cytolysis. A highly synergistic cytotoxic effect of the combination of TRAIL with any of the antiblastic used in this study was detected in the chemoresistant cells. This effect was associated with mitochondrial disassemblage and dependent on caspase activation CONCLUSIONS: The combination of TRAIL with conventional anticancer drugs may prove to be useful in the treatment of antiapoptotic Bcl-2 family proteins-expressing malignancies.

Amino Acid Chloromethyl Ketones↗

PubMed2006

Aspirin reduces the outcome of anticancer therapy in Meth A-bearing mice through activation of AKT-glycogen synthase kinase signaling.

Aspirin displays, at millimolar concentrations, several mechanisms independent from its ability to inhibit cyclooxygenases. Occasionally, the mechanisms displayed in vitro have been clearly related to an effect of clinical relevance in vivo. An expanding literature has been focusing on the cytoprotective effect of aspirin in neurodegenerative disorders and the activation of AKT pathway in neuroprotection and induction of resistance to anticancer drugs. In this work, we tested the ability of aspirin to activate the AKT survival pathway in methylcholanthrene-induced fibrosarcoma cells (Meth A) transplanted into BALB/c nude mice and the clinical effect of aspirin cotreatment during etoposide (VP-16)-based anticancer therapy. We found that cotreatment with aspirin reduced VP-16-induced apoptosis and activated AKT in vitro and in vivo. In Meth A-bearing mice, aspirin administration also activated glycogen synthase kinase-3 and reduced the activity and the efficacy of anticancer therapy in VP-16 cotreated animals. Our data suggest that the antiapoptotic effect of aspirin operates in vivo through the activation of AKT-glycogen synthase kinase pathway causing a decrease in the outcome of VP-16-based therapy. These findings could have clinical relevance in treatment of human malignancies.

Animals↗

PubMed2006

Ratiometric dosing of anticancer drug combinations: controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice.

Anticancer drug combinations can act synergistically or antagonistically against tumor cells in vitro depending on the ratios of the individual agents comprising the combination. The importance of drug ratios in vivo, however, has heretofore not been investigated, and combination chemotherapy treatment regimens continue to be developed based on the maximum tolerated dose of the individual agents. We systematically examined three different drug combinations representing a range of anticancer drug classes with distinct molecular mechanisms (irinotecan/floxuridine, cytarabine/daunorubicin, and cisplatin/daunorubicin) for drug ratio-dependent synergy. In each case, synergistic interactions were observed in vitro at certain drug/drug molar ratio ranges (1:1, 5:1, and 10:1, respectively), whereas other ratios were additive or antagonistic. We were able to maintain fixed drug ratios in plasma of mice for 24 hours after i.v. injection for all three combinations by controlling and overcoming the inherent dissimilar pharmacokinetics of individual drugs through encapsulation in liposomal carrier systems. The liposomes not only maintained drug ratios in the plasma after injection, but also delivered the formulated drug ratio directly to tumor tissue. In vivo maintenance of drug ratios shown to be synergistic in vitro provided increased efficacy in preclinical tumor models, whereas attenuated antitumor activity was observed when antagonistic drug ratios were maintained. Fixing synergistic drug ratios in pharmaceutical carriers provides an avenue by which anticancer drug combinations can be optimized prospectively for maximum therapeutic activity during preclinical development and differs from current practice in which dosing regimens are developed empirically in late-stage clinical trials based on tolerability.

Animals↗

PubMed1986

Recent studies on the anticancer activities of mistletoe (Viscum album) and its alkaloids.

Detailed methods for in vitro/in vivo evaluation of anticancer drugs, with special reference to mistletoe extracts, have been reviewed. Mistletoe extracts have been shown to possess significant antitumor activity, in vivo, against murine tumors, Lewis lung carcinoma, colon adenocarcinoma 38 and C3H mammary adenocarcinoma 16/C. Methods for the extraction of biologically active alkaloids from mistletoe and their anticancer activities are presented. The possible origin of alkaloids in mistletoe plants, and their contributions towards a mechanism of anticancer activities of mistletoe extracts, are proposed.

Alkaloids↗

PubMed1984

Combination of anticancer agents with folic acid in the treatment of murine leukaemia P388.

Folic acid (FA) was combined with anticancer agents such as (i) antimetabolites like methotrexate (MTX), 5-fluorouracil (5-FU), arabinosyl cytosine (Ara-C) and 6-mercaptopurine (6-MP); (ii) plant-derived mitotic inhibitor, vincristine (VCR), and (iii) an antibiotic, mitomycin C (Mit-C). This combination modality was used for the treatment of P388 lymphocytic leukaemia. Large doses of FA were administered to the tumour-bearing mice either prior to or simultaneously with different anticancer agents. Pre-treatment with FA significantly improved the therapeutic efficacy of 5-FU, Ara-C and Mit-C; while MTX was more effective when given simultaneously with FA. The efficacy of 6-MP and VCR was not enhanced by FA when tested similarly. Large doses of FA can potentiate the activity of certain anticancer agents when administered to P388-bearing mice at critical times that vary according to the particular drug used.

Animals↗

PubMed1975

Cytocidal action of anticancer antigens: evaluation of the sensitivity of cultured animal and human cancer cells.

The cultured cell lines Yoshida ascites sarcoma, L-1210 mouse leukemia, OAT cell line derived from human lung cancer of the oat cell type, and P3HR-1 cell line derived from Burkitt's lymphoma have been used for the cell-killing kinetics study of anticancer agents and evaluation of the sensitivity of cells using the soft agar cloning assay method. It has been found that there are 2 types of actions: 1) Type I (cytocidal and concentration-dependent action). The dose survival curves of Type I agents fit the equation log S=log nminuskD (S, surviving fraction; D, concentration of agents; n and k are constant). The sensitivity of cells can be expressed by mean lethal dose 90% (MLD90=1/k). Four cell lines were compared on this basis, and some problems concerning the chemotherapy of human cancer are discussed. Alkylating agents and anticancer antibiotics belonged to this group.2) Type II (cytostatic and time-dependent action). The dose survival curves fit the Gompertz equation S=exp[(minusbeta/alpha)(1minus e-aD)] (beta, population reduction parameter; alpha, constant). The exposure survival curve is negative exponential, indicating that exposure time rather than concentration is the key fo effective cell killing of Type II agents. Difficulties in expression of sensitivity to Type II agents are discussed. Antimetabolites, Vinca alkaloids, and L-asparaginase belonged to this group. The cell-killing kinetics of anticancer agents and comparison of the sensitivity of cells may provide some indications not only of optimal dosage schedules but also of a new approach in screening systems for truly effective agents for human cancer.

Alkylating Agents↗

PubMed1994

Recent advances in the development of anticancer drugs that act against signalling pathways.

Cancer can be considered a disease of deranged intracellular signalling. The intracellular signalling pathways that mediate the effects of oncogenes on cell growth and transformation present attractive targets for the development of new classes of drugs for the prevention and treatment of cancer. This is a new approach to developing anticancer drugs and the potential, as well as some of the problems, inherent in the approach are discussed. Anticancer drugs that produce their effects by disrupting signalling pathways are already in clinical trial. Some properties of these drugs, as well as other inhibitors of signalling pathways under development as potential anticancer drugs, are reviewed.

Animals↗

PubMedDate not supplied

Reactions and interactions in handling anticancer drugs.

The clinical toxicity of anticancer drugs has been well documented with regard to the adverse effects of treatment in patients. However, many of these drugs have a direct irritant effect on the skin, eyes, mucous membranes, and other tissues. Handled without due care, especially when being prepared for injection, most cytotoxic drugs can cause local toxic or allergic reactions; they also present hazards of carcinogenicity and mutagenicity. This spectrum of potential risk should be kept in mind by personnel administering or handling these drugs, especially in oncology units where just a few individuals may routinely and frequently reconstitute many doses of cytotoxic agents. This is work in which the hospital pharmacist should and must be involved; indeed, many of the techniques and skills required are identical with those used in standard aseptic procedures for preparing pharmaceutical products. Pharmacy departments should take the initiative in making hospital staff aware of the potential risks of handling neoplastic agents, and they should spearhead a multidisciplinary assessment for producing local guidelines for working with these drugs. This article warns practitioners about the inherent dangers of these practitioner-drug interactions and suggests ways in which they may be reduced. Information is given in tabular form regarding recommended procedures for reconstituting 24 anticancer drugs and precautions to protect the personnel handling them, especially when there is spillage of powdered or liquid drugs. Also, guidelines are given about incompatibilities with admixtures of such drugs, and the literature is reviewed relative to recent developments in hospital pharmacy departments where reconstitution of anticancer drugs has been incorporated into existing intravenous fluid preparation/admixture units. Not only has this been shown to be safer and more effective in terms of time and labor, but also it has cut the cost of injectable cytotoxic drugs by an appreciable percentage.

Antineoplastic Agents↗

PubMed2003

B-cell-specific transcription factor BACH2 modifies the cytotoxic effects of anticancer drugs.

The transcription factor Bach2, a member of the CNC family of proteins, binds to the Maf recognition element (MARE) by forming homodimers or dimerizing with small Maf transcription factors. Bach2-expressing cells show reduced proliferation and undergo spontaneous cell death. The inhibition of BCR/ABL tyrosine kinase activity by STI571 in chronic myeloid leukemia (CML) cell lines and CD34+ cells from patients with CML in lymphoid crisis results in induction of BACH2 expression. We show here that BACH2 modifies the in vitro cytotoxicity of anticancer drugs. The cytotoxic effects of commonly used anticancer agents were studied by overexpression of BACH2 in RAJI lymphoid cells, a cell line that does not express endogenous BACH2. Cell growth inhibition was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Clones overexpressing BACH2 were more sensitive to etoposide, doxorubicin, and cytarabine than control RAJI cells, whereas there were no significant differences in the sensitivity of either cells to methotrexate or vincristine. Interestingly, we found that the former drugs were oxidative stressors that induced the nuclear accumulation of BACH2. In contrast, methotrexate or vincristine did not induce production of intracellular reactive oxygen species (ROS) and nuclear accumulation of BACH2. These results, coupled with our previous data showing that BACH2 promotes oxidative stress-induced cell death, suggest that combination chemotherapy involving STI571 and anticancer drugs that produce ROS may be of benefit in the treatment of Philadelphia chromosome 1 (Ph1)-positive leukemia.

Active Transport, Cell Nucleus↗