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PubMed1993

Antimetastatic effect by anti-adhesion therapy with cell-adhesive peptide of fibronectin in combination with anticancer drugs.

We have investigated the therapeutic effect of CH-271 fusion polypeptide containing both cell-binding domain (C-274) and heparin-binding domain (H-271) of fibronectin in combination with anticancer drugs such as doxorubicin (DOX) or mitomycin C (MMC) on tumor metastasis of different types of tumors. CH-271 fusion polypeptide alone significantly inhibited both liver and lung metastasis when it was co-injected with L5178Y-ML25 T-lymphoma, RAW117-H10 B-lymphoma or B16-BL6 melanoma cells, and spontaneous lung metastasis of B16-BL6 melanoma cells when administered i.v. seven times before or after surgical excision of the primary tumors. Combined treatments with CH-271 and either DOX or MMC significantly inhibited liver and lung metastasis of lymphoma or melanoma cells respectively, as compared with either treatment alone or the untreated control. Administrations of CH-271 and DOX in combination substantially prolonged the survival time of mice injected i.v. with L5178Y-ML25 cells. CH-271 or DOX was effective for inhibiting the invasion of L5178Y-ML25 cells into Matrigel in a concentration-dependent manner. Our previous study has shown that CH-271-mediated inhibition of tumor invasion may be due in part to the anti-cell adhesive property without affecting the cell growth, whereas the anti-invasive effect of DOX was established to have resulted from the growth inhibition of tumor cells. Moreover, the combination of CH-271 with DOX provided a more effective inhibition of tumor invasion into Matrigel than did either alone. Thus, we have demonstrated that the combination of anti-cell adhesive CH-271 and anticancer drugs such as DOX or MMC, i.e. anti-adhesion therapy and chemotherapy, is a new approach that offers enhanced (additive) inhibitory effects on tumor metastasis and invasion.

Amino Acid Sequence↗

PubMed1995

Establishment and characterization of acquired resistance to platinum anticancer drugs in human ovarian carcinoma cells.

To investigate differences in resistance to cis-diamminedichloroplatinum(II) (CDDP) and diammine (1,1-cyclobutanecarboxylato)platinum(II) (CBDCA), and their newly developed derivative, ((-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato)platinum (II) (DWA2114R), four types of resistant cell lines were established from a parental cell line (NOS2) of a serous cystadenocarcinoma of the ovary. The cross-resistance of CDDP-resistant cells (NOS2CR1 and NOS2CR2) to DWA2114R was slight (only 25% of the resistance to CDDP), and no cross-resistance was observed to anticancer drugs other than the CDDP derivative, except to camptothecin (CPT-11) in the case of NOS2CR2 cells. The cross-resistance of CBDCA-resistant cells (NOS2CBR) to DWA2114R was slight (only about 1/3 of the resistance to CBDCA), and no cross-resistance was observed among anticancer drugs other than the CDDP derivative. On the other hand, DWA2114R-resistant cells (NOS2DR) showed a high cross-resistance to CDDP, CBDCA, etoposide (VP-16), and CPT-11. Intracellular accumulations of CDDP and CBDCA were markedly reduced in NOS2CR1, NOS2CR2, and NOS2CBR cells compared to those in NOS2 cells, but were reduced only slightly in NOS2DR cells. Intracellular accumulation of DWA2114R was reduced somewhat in the four types of resistant cells. Glutathione S-transferase activity was not increased in any of the four types of resistant cells, and intracellular GSH concentration was increased only in NOS2CR2 cells (by 2.6 fold). From these results, we consider that the resistance mechanisms against CDDP and CDBCA are similar, and reduction of intracellular drug accumulations is a significant factor. Resistance to DWA2114R differed from resistance to CDDP and CBDCA in both cross-resistance spectrum and resistance mechanism, indicating that reduction in intracellular drug accumulation is not the major resistance mechanism.

Camptothecin↗

PubMed1996

Evaluation of the relative cytotoxic effects of anticancer agents in serum-supplemented versus serum-free media using a tetrazolium colorimetric assay.

Most cell culture and in vitro drug sensitivity assays utilize serum-supplemented media (SSM). However, fully defined serum-free media (SFM) offer several advantages and are being used increasingly for initiation and maintenance of cell cultures. Because serum inhibits the in vitro cytotoxicity of certain antineoplastic agents, we investigated the inter-relationships between medium type, cell proliferation and cytotoxic effect. Twenty-four human lung cancer cell lines were tested with nine anticancer agents in both media types. A semi-automated tetrazolium (MTT) colorimetric assay was used for assaying cell survival. Cell lines initiated and maintained in SFM preferentially proliferated in that medium type or proliferated equally well in both media types. In contrast, cell lines established in SSM varied considerably in their medium of preference. There appeared to be a direct correlation or trend between cell proliferative rate and cytotoxicity of all drugs with the possible exceptions of methotrexate and carmustine. In general, the cell lines were more sensitive to anticancer agents when they were exposed in the culture medium in which they preferentially proliferated. Therefore, to determine the influence of culture media on cytotoxicity, we analyzed the data only from lines that replicated equally efficiently in both media. After correction for cell proliferative rate, SSM had a negative effect on the cytotoxic action of some drugs (especially methotrexate, 5-fluorouracil and, to a lesser extent, mitomycin-C). Our results demonstrate that fully defined SFM may be suitable for initiating cell lines and for use in in vitro cytotoxicity assays for selection of individualized therapy or for screening of new anti-neoplastic agents, and thus may increase the number of antineoplastic agents that can be tested satisfactorily.

Antineoplastic Agents↗

PubMed2001

Anticancer drug-mediated induction of multidrug resistance-associated genes and protein kinase C isozymes in the T-lymphoblastoid cell line CCRF-CEM and in blasts from patients with acute lymphoblastic leukemias.

The major determinants mediating drug resistance in acute lymphoblastic leukemias (ALL) unresponsive to chemotherapy, are still unclear. For example, it is still unknown whether selection or induction processes are responsible for drug resistance here or whether protein kinase C (PKC) isozymes contribute to the resistant phenotype. Therefore, inducibility of resistance factors or PKC isozymes genes was examined in CCRF-CEM cells treated with diverse anticancer drugs--adriamycin, camptothecin, etoposide or vincristine--at sublethal concentrations for 24 h. MDR1, MRP1, LRP and PKC isozyme alpha, beta(1), beta(2), epsilon, iota, eta, theta, zeta gene expression was determined by cDNA-PCR. We found significant dose-dependent, mostly combined, induction of the MDR1, MRP1 and LRP genes. Significantly enhanced gene expression of the majority of PKC isozyme genes was found after treatment with camptothecin. PKCzeta was upregulated throughout by each anticancer drug applied in this setting. A series of selected CCRF-CEM-derived multidrug resistance (MDR) sublines also showed enhanced expression of the PKC isozymes compared to the parental cell line. MDR1 and PKCeta gene expression levels were correlated highly significantly. Blasts from two patients with ALL during the first week of monotherapy with steroids revealed combined induction of the MDR1, multidrug resistance-associated protein 1 (MRP1), lung cancer resistance-related protein (LRP) and most PKC isozymes, predominantly PKCzeta. Another patient with T-ALL, who failed to respond to four months of intensive chemotherapy, showed an enhanced MRP1 gene expression combined with markedly overexpression of PKCeta and PKCtheta. Furthermore, the camptothecin and etoposide-mediated induction of resistance factors in the CCRF-CEM cell line could be suppressed by staurosporine, a rather unspecific inhibitor of protein kinases. However, selective inhibitors of PKC isozymes (bisindolylmaleimide GO 6850, indolocarbazole GO 6976) produced no significant effects here. Therefore, the PKC isozymes eta, theta and zeta are of interest as potential targets to overcome drug resistance in ALL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Incorporation of the anticancer agent KRN5500 into polymeric micelles diminishes the pulmonary toxicity.

KRN5500 is a highly active new semi-synthetic water-insoluble anticancer agent. The only mechanism of anticancer activity of KRN5500 described so far is an inhibitory effect on protein synthesis. At the time of writing, a phase I clinical trial is under way at the National Cancer Center Hospital, Tokyo, and at the National Cancer Institute in the USA. Although preclinical data did not indicate lung toxicity, some cases of severe pulmonary disorder were reported in the phase I clinical trials. This study has been conducted to examine whether incorporation of KRN5500 into polymeric micelles (KRN/m) could reduce the toxic effects caused by the current formulation of KRN5500. The in vitro and in vivo antitumor activities of KRN5500 and KRN/m were compared. Pulmonary toxicity of KRN5500 and KRN/m was studied using a bleomycin (BLM)-induced lung injury rat model. In BLM-rats, extensive pulmonary hemorrhage with diapedesis was observed with KRN5500 i.v. bolus injection at the dose of 3 mg/kg, which is equivalent to 21.0 mg/m2 (level 5) of the Japanese phase I trial. However, toxicity was not observed when rats were administered KRN / m at the equivalent dose to KRN5500 in potency. Electron microscopy of the lung treated with KRN5500 showed disruption of the alveolar type II membrane with release of lamellar debris. Furthermore, in vivo, KRN/m showed similar antitumor activity to KRN5500. These results indicate that KRN/m may be useful for reducing the pulmonary toxicity associated with the current formulation of KRN5500, while fully maintaining its antitumor activity.

Animals↗

PubMed2002

Sensitivity to anticancer agents and resistance mechanisms in clear cell carcinoma of the ovary.

We conducted the present study to determine the chemoresistance mechanisms in clear cell carcinoma of the ovary (CCC). Five human CCC cell lines (HAC-2, RMG-I, RMG-II, KK, and KOC-7c) were used in this study. The sensitivity of the cells to the anticancer agents was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and we assessed drug sensitivity by calculating assay area under the curve (AUC) for each agent. The expression of multi-drug resistance genes (MDR-1, MRP-1, MRP-2) was detected by reverse transcription-polymerase chain reaction (RT-PCR). Glutathione (GSH) concentration was measured by an enzymatic assay. Topoisomerase (topo) I activity was assayed in terms of relaxation of supercoiled plasmid substrate DNA. The IC(50) to anticancer agents ranged widely. The assay AUC indicated that 3 of 5 cell lines (RMG-I, RMG-II, and KK) were sensitive to paclitaxel (PTX), 3 (HAC-2, RMG-I, and RMG-II) were sensitive to 7-ethyl-10-hydroxycamptothecin (SN-38), which is an active metabolite of camptothecin (CPT-11), and only one (HAC-2) was sensitive to cisplatin (CDDP). All cell lines were resistant to mitomycin-C (MMC) and etoposide (VP-16). The MRP-1 gene was detected in all cell lines. Only one cell line showed both MRP-2 and MDR-1 gene expression. Except for HAC-2 cells, expression of MRP genes was related to CDDP resistance, and MDR-1 gene expression was associated with PTX resistance. GSH concentrations increased after exposure to CDDP or MMC in all cell lines. There was a significant correlation between topo-I enzymatic activity and the response to SN-38. The present study revealed several resistance mechanisms in CCC and the results suggested that PTX and CPT-11 might be effective agents to treat CCC.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Breast cancer resistance protein: molecular target for anticancer drug resistance and pharmacokinetics/pharmacodynamics.

Breast cancer resistance protein (BCRP) is a half-molecule ATP-binding cassette transporter that forms a functional homodimer and pumps out various anticancer agents, such as 7-ethyl-10-hydroxycamptothecin, topotecan, mitoxantrone and flavopiridol, from cells. Estrogens, such as estrone and 17beta-estradiol, have been found to restore drug sensitivity levels in BCRP-transduced cells by increasing the cellular accumulation of such agents. Furthermore, synthetic estrogens, tamoxifen derivatives and phytoestrogens/flavonoids have now been identified that can effectively circumvent BCRP-mediated drug resistance. Transcellular transport experiments have shown that BCRP transports sulfated estrogens and various sulfated steroidal compounds, but not free estrogens. The kinase inhibitor gefitinib inhibited the transporter function of BCRP and reversed BCRP-mediated drug resistance both in vitro and in vivo. BCRP-transduced human epidermoid carcinoma A431 (A431/BCRP) and BCRP-transduced human non-small cell lung cancer PC-9 (PC-9/BCRP) cells showed gefitinib resistance. Physiological concentrations of estrogens (10-100 pM) reduced BCRP protein expression without affecting its mRNA levels. Two functional polymorphisms of the BCRP gene have been identified. The C376T (Q126Stop) polymorphism has a dramatic phenotype as active BCRP protein cannot be expressed from a C376T allele. The C421A (Q141K) polymorphism is also significant as Q141K-BCRP-transfected cells show markedly low protein expression levels and low-level drug resistance. Hence, individuals with C376T or C421A polymorphisms may express low levels of BCRP or none at all, resulting in hypersensitivity of normal cells to BCRP-substrate anticancer agents. In summary, both modulators of BCRP and functional single nucleotide polymorphisms within the BCRP gene affect the transporter function of the protein and thus can modulate drug sensitivity and substrate pharmacokinetics and pharmacodynamics in affected cells and individuals.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2006

The historical analysis of aspirin discovery, its relation to the willow tree and antiproliferative and anticancer potential.

For several millennia, the willow tree and salicin have been associated with salicylic acid, the key precursor molecule that has contributed to the discovery of acetylsalicylic acid, traded as aspirin. These molecules have been shown to possess phyto- and chemotherapeutic activities as analgesic drugs. In recent decades, aspirin has become the focus of extensive investigation into antiproliferative and anticancer activities. The historical steps that led to the discovery of aspirin, and its antiproliferative and anticancer potential are highlighted in this review.

Animals↗

PubMedDate not supplied

Survivin as a target for new anticancer interventions.

Survivin is a member of the inhibitor of apoptosis protein (IAP) family, that has been implicated in both control of cell division and inhibition of apoptosis. Specifically, its anti-apoptotic function seems to be related to the ability to directly or indirectly inhibit caspases. Survivin is selectively expressed in the most common human neoplasms and appears to be involved in tumor cell resistance to some anticancer agents and ionizing radiation. On the basis of these findings survivin has been proposed as an attractive target for new anticancer interventions. Several preclinical studies have demonstrated that down-regulation of survivin expression/function, accomplished through the use of antisense oligonucleotides, dominant negative mutants, ribozymes, small interfering RNAs and cyclin-dependent kinase inhibitors, increased the apoptotic rate, reduced tumor-growth potential and sensitized tumor cells to chemotherapeutic drugs with different action mechanisms and gamma-irradiation in in vitro and in vivo models of different human tumor types.

Antineoplastic Agents↗

PubMed2006

The Saccharomyces cerevisiae orthologue of the human protein phosphatase 4 core regulatory subunit R2 confers resistance to the anticancer drug cisplatin.

The anticancer agents cisplatin and oxaliplatin are widely used in the treatment of human neoplasias. A genome-wide screen in Saccharomyces cerevisiae previously identified PPH3 and PSY2 among the top 20 genes conferring resistance to these anticancer agents. The mammalian orthologue of Pph3p is the protein serine/threonine phosphatase Ppp4c, which is found in high molecular mass complexes bound to a regulatory subunit R2. We show here that the putative S. cerevisiae orthologue of R2, which is encoded by ORF YBL046w, binds to Pph3p and exhibits the same unusually high asymmetry as mammalian R2. Despite the essential function of Ppp4c-R2 in microtubule-related processes at centrosomes in higher eukaryotes, S. cerevisiae diploid strains with homozygous deletion of YBL046w and two or one functional copies of the TUB2 gene were viable and no more sensitive to microtubule-depolymerizing drugs than the control strain. The protein encoded by YBL046w exhibited a predominantly nuclear localization. These studies suggest that the centrosomal function of Ppp4c-R2 is not required or may be performed by a different phosphatase in yeast. Homozygous diploid deletion strains of S. cerevisiae, pph3Delta, ybl046wDelta and psy2Delta, were all more sensitive to cisplatin than the control strain. The YBL046w gene therefore confers resistance to cisplatin and was termed PSY4 (platinum sensitivity 4). Ppp4c, R2 and the putative orthologue of Psy2p (termed R3) are shown here to form a complex in Drosophila melanogaster and mammalian cells. By comparison with the yeast system, this complex may confer resistance to cisplatin in higher eukaryotes.

Amino Acid Sequence↗

PubMed2004

Effects of anticancer chemotherapeutic drugs on the acetylcholine receptor-operated potassium current in guinea pig atrial myocytes.

The effects of 7 anticancer chemotherapeutic drugs on the muscarinic acetylcholine receptor-operated potassium current (I(K.ACh)) in guinea pig atrial myocytes were investigated using the whole cell patch clamp technique. Doxorubicin, pirarubicin, and mitoxantrone inhibited the carbachol-induced I(K.ACh) in a concentration-dependent manner in atrial cells at a holding potential of -40 mV. IC50 values of doxorubicin, pirarubicin, and mitoxantrone for the carbachol-induced I(K.ACh) were 7.7 microM, 3.7 microM, and 9.1 microM, respectively. Pirarubicin inhibited the adenosine-induced and the GTPgammaS-induced I(K.ACh) in a concentration-dependent manner (IC50=6.0 and 5.1 microM, respectively). Doxorubicin and mitoxantrone up to 100 microM did not have an influence on the adenosine-induced I(K.ACh). Doxorubicin did not affect the GTPgammaS-induced I(K.ACh). Mitoxantrone 100 microM inhibited the current only by 25%. For concentrations up to 100 microM, anticancer drugs that have chemical structures entirely different from that of doxorubicin, i.e., 5-fluorouracil, 6-mercaptopurine, cyclophosphamide, and actinomycin D, did not have an influence on the carbachol-induced I(K.ACh). Doxorubicin and chemically related compounds possess anticholinergic effects mediated via an inhibitory action on I(K.ACh) by different underlying molecular mechanisms. Doxorubicin and mitoxantrone may inhibit I(K.ACh) by the blockade of muscarinic receptors, whereas pirarubicin may inhibit the current not only via blocking the muscarinic receptors but also by depressing the functions of the K+ channel itself and/or GTP-binding proteins.

Animals↗

PubMed2005

Anticancer activity of sodium caffeate and its mechanism.

AIM: To study the anticancer activity of sodium caffeate (SC). METHODS: A nucleoside transport assay was used to analyze the inhibitory effects of SC on nucleoside rescue. The MTT assay was used to measure cell proliferation. Flow cytometry was used to measure the apoptosis of BEC-7402 induced by SC and the cell cycle distribution change. Western blotting analysis was employed to investigate Bcl-2, caspase and Bax expression. Intracellular Ca2+ and mitochondrial membrane potential were determined by flow cytometry. In vivo anti-tumor activity was measured using a tumor transplantation model in mice. RESULTS: SC inhibited the nucleoside transport of BEL-7402 cells with an IC(50) of 1.02 microg/mL. SC inhibited tumor cell proliferation with an IC50 between 100 microg/mL and 200 microg/mL. SC induced BEL-7402 cell apoptosis in a time- and dose-dependent manner, which was induced by arresting cells in S phase. The in vivo study showed that tumor growth was inhibited in a dose-dependent manner. Activated caspase-3 and Bax expression were up-regulated after treatment with SC, while Bcl-2 expression was down-regulated. Intracellular Ca2+ was increased while mitochondrial membrane potential was decreased by SC. CONCLUSION: SC is a new anticancer agent with promising potential.

Animals↗

PubMed1985

Design of anticancer drugs using modeling techniques.

Flexibility of intercalation site geometries within a B-DNA helix was investigated in the twist-shift plane using energy minimization methods. The parameters optimized included sugar conformation, the glycosidic angles and phosphodiester torsion angles. Our calculations show several regions of energetically favorable intercalation geometries in the twist-shift plane. Modeling studies using interactive computer graphics and electrostatic potential surface compatibility provided initial hypotheses for the structures of the drug-DNA complexes. These hypotheses were supported and extended by energy minimizations of these complexes. Binding positions, conformational features and relative minimum binding energies of two anticancer drugs, mitoxantrone and bisantrene, were computed for intercalation complexes with DNA in the theoretically defined intercalation sites. Mitoxantrone intercalates DNA from the minor groove and the side chain OH or NH groups are involved in hydrogen bonds with the main chain phosphate groups of DNA, thereby cross-linking the complementary strands. The hydroxyl groups of mitoxantrone can also participate in hydrogen bonding with phosphate oxygens of another chain, thereby cross-linking DNA helices. Bisantrene intercalates DNA favorably from the major groove and the NH group of the dihydroimidazole ring can participate in hydrogen bonding with the phosphate oxygens of the backbone. These models are consistent with the physicochemical and electron microscopic studies of the interaction of mitoxantrone and bisantrene with DNA. Our results are now being used to guide the design of novel anticancer drugs that should interact with DNA in a manner similar to that proposed for our representative drugs.

Anthracenes↗

PubMed2000

Modulation of anticancer cytokines IL-2 and IL-12 by melatonin and the other pineal indoles 5-methoxytryptamine and 5-methoxytryptophol in the treatment of human neoplasms.

Lymphocyte number still remains one of the most important immune parameters predicting the prognosis of advanced cancer patients. IL-2 and IL-12 are the main antitumor cytokines in humans, and their effect is modulated by the neuroendocrine system, mainly by the pineal gland through the circadian release of melatonin (MLT) and perhaps that of other indole hormones, such as 5-methoxytryptamine (5-MTT), and 5-methoxytryptophol (5-MTP). MLT has been proven to exert important antitumor immunomodulating effects, whereas the possible immunomodulatory properties of the other pineal indoles are still controversial. In an attempt to better define the pineal neuroendocrine regulation of the anticancer cytokine network, we have evaluated in metastatic solid-tumor patients the effects on lymphocyte number induced by different neuroimmune regimens, consisting of MLT alone (20 mg/day orally in the evening), subcutaneous (s.c.) low-dose IL-2 alone (3 MIU/day in the evening for 6 days/week), s.c. low-dose IL-12 alone (0.5 mcg/kg once/week in the morning), IL-12 plus MLT, IL-2 plus MLT, and IL-2 plus MLT plus 5-MTT (10 mg/day orally in the afternoon) plus 5-MTP (5 mg/day orally at noon). The results showed the following evidence: (1) MLT alone is unable to induce lymphocytosis; (2) MLT significantly enhances IL-2-induced lymphocytosis; (3) IL-12 alone determines lymphocytopenia, which can be reversed by MLT; (4) IL-2 plus IL-12 induces a very pronounced lymphocytosis, which can be further amplified by MLT; (5) a total pineal endocrine replacement therapy with MLT, 5-MTT, and 5-MTP further increases IL-2-induced lymphocytosis with respect to MLT plus IL-2 alone. Therefore, this study confirms that IL-2- and IL-12-dependent anticancer immunity is under a pineal modulation.

5-Methoxytryptamine↗

PubMed1989

Photosensitization of anticancer agents--8. One-electron reduction of mitoxantrone: an EPR and spectrophotometric study.

An efficient method of one-electron reduction of the anticancer agent mitoxantrone is described. The method depends on illumination of a suitable photosensitizer absorbing blue light [acriflavine, anthrapyrazole, or Ru(bpy)2+(3)] in the presence of the drug and an electron donor, such as NAD(P)H, in deaerated solutions. An EPR spectrum, assigned to a semiquinone of mitoxantrone, is generated under these conditions and identified by spectral simulation. Decay of this species, attributed to a radical-radical reaction, gives a second order rate constant of 1.7 x 10(2) M-1 s-1 in organic media [dimethylsulfoxide (DMSO)/pH 8 buffer, 1:1 vol/vol] but is more rapid (approximately 10(4) M-1 s-1) in aqueous media under comparable conditions. The considerably decreased lifetime of the mitoxantrone radical at pH 5 is attributed to an additional electron transfer, promoted by protonation of the radical, and/or to an accelerated recombination of neutral radicals, leading to an EPR-silent species. Parallel spectrophotometric studies on the generation of the mitoxantrone reduced species by photosensitized reduction are described. The method offers convenient access to a key radical species involved in the metabolism and possible mode of action of this clinical anticancer agent.

Electron Spin Resonance Spectroscopy↗

PubMed2004

Intrinsic and acquired forms of resistance against the anticancer ruthenium compound KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A).

KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A) is a metal complex with promising anticancer activity. Since chemoresistance is a major obstacle in chemotherapy, this study investigated the influence of several drug resistance mechanisms on the anticancer activity of KP1019. Here we demonstrate that the cytotoxic effects of KP1019 are neither substantially hampered by overexpression of the drug resistance proteins multidrug resistance-related protein 1, breast cancer resistance protein, and lung resistance protein nor the transferrin receptor and only marginally by the cellular p53 status. In contrast, P-glycoprotein overexpression weakly but significantly (up to 2-fold) reduced KP1019 activity. P-glycoprotein-related resistance was based on reduced intracellular KP1019 accumulation and reversible by known P-glycoprotein modulators. KP1019 dose dependently inhibited ATPase activity of P-glycoprotein with a K(i) of approximately 31 microM. Furthermore, it potently blocked P-glycoprotein-mediated rhodamine 123 efflux under serum-free conditions (EC(50), approximately 8 microM), however, with reduced activity at increased serum concentrations (EC(50) at 10% serum, approximately 35 microM). Moreover, P-glycoprotein-mediated daunomycin resistance could only be marginally restored by KP1019 in serum-containing medium, also indicating an influence of serum proteins on the interaction between KP1019 and P-glycoprotein. Acquired KP1019 resistance was investigated by selecting KB-3-1 cells against KP1019 for more than 1 year. Only an approximately 2-fold KP1019 resistance could be induced, which unexpectedly was not due to overexpression of P-glycoprotein or other efflux pumps. Accordingly, KP1019-resistant cells did not display reduced drug accumulation. Their unique cross-resistance pattern confirmed an ABC transporter-independent resistance phenotype. In summary, the likeliness of acquiring insensitivity to KP1019 during therapy is expected to be low, and resistance should not be based on overexpression of drug efflux transporters.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Resistance of human astrocytoma cells to apoptosis induced by mitochondria-damaging agents: possible implications for anticancer therapy.

The success of anticancer chemotherapy is often hampered by resistance to apoptosis, which may depend on defects in intracellular cell death pathways. Characterizing the alterations of these pathways is a prerequisite for developing alternative and effective antitumoral strategies. Here, we investigated the susceptibility of a human astrocytoma cell line, ADF, to apoptotic cell death induced by mitochondria-damaging agents. Neither the anticancer agent betulinic acid nor the "mitochondriotropic" poisons 2-deoxy-d-ribose and potassium cyanide induced apoptosis of these cells, despite induction of highly significant mitochondrial depolarization, eventually resulting in necrotic death. Resistance to apoptosis was not due to presence of the multidrug resistance pump or to impaired expression of caspase-8, caspase-9, or "executioner" caspase-3. Cloning of caspase-9 revealed the presence of full-length caspase-9alpha and a short variant (caspase-9beta), which, in other tumors, acts as a dominant negative of the long isoform. All analyzed clones showed a point mutation in the prodomain region that is known to interact with mitochondria-released factors. Thus, in these human astrocytoma cells, mitochondria-damaging agents induce a regulated form of mitochondrial-dependent necrotic cell death (oncosis). Resistance to apoptosis is due to an intrinsic defect of caspase-9, leading to inhibition of enzyme activation and/or impaired interaction with proteins released from depolarized mitochondria. These results may have implications for developing strategies aimed at overcoming tumor resistance to chemotherapy.

Amino Acid Sequence↗

PubMed2006

A boronic-chalcone derivative exhibits potent anticancer activity through inhibition of the proteasome.

Chalcones and their derivatives have been shown to have potent anticancer activity. However, the exact mechanisms of cytotoxic activity remain to be established. In this study, we have evaluated a series of boronic chalcones for their anticancer activity and mechanisms of action. Among the eight chalcone derivatives tested, 3,5-bis-(4-boronic acid-benzylidene)-1-methyl-piperidin-4-one (AM114) exhibited most potent growth inhibitory activity with IC50 values of 1.5 and 0.6 microM in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and colony formation assay, respectively. The cytotoxic activity of AM114 was shown to be associated with the accumulation of p53 and p21 proteins and induction of apoptosis. Mechanistic studies showed that AM114 treatment inhibited the chymotrypsin-like activity of the 20S proteasome in vitro, leading to a significant accumulation of ubiquitinated p53 and other cellular proteins in whole cells. In vitro studies showed that AM114 did not significantly disrupt the interaction of p53 and murine double minute 2 protein. It is noteworthy that AM114 as a single agent was preferentially toxic to cells with wild-type p53 expression, whereas combination of this compound with ionizing radiation (IR) significantly enhanced the cell-killing activity of IR in both wild-type p53 and p53-null cells. Together, these results indicate that the boronic chalcone derivative AM114 induces significant cytotoxic effect in cancer cells through the inhibition of the cellular proteasome and provide a rationale for the further development of this class of compounds as novel cancer chemotherapeutic agents.

Antineoplastic Agents↗