piperidines and (2-(4-methoxyphenyl)-4-quinolinyl)(2-piperidinyl)methanol

P-glycoprotein (P-gp) is a member of ATP-binding cassette (ABC) superfamily which extrudes chemotherapeutic agents out of the cell. Suppression of this efflux activity has been the subject of numerous attempts to develop P-gp inhibitors. The aim of this review is to present up-to-date information on the structural and functional aspects of P-gp and its known inhibitors. The data presented also provide some information on drug discovery approaches for candidate P-gp inhibitors. Nucleotide-binding domains (NBDs) and drug-binding domains (DBDs) have been extensively studied to gain more information about P-gp inhibition and it looks that the ATPase activity of this pump has been the most attractive target for designing inhibitors. Hydrophobic and π-π (aromatic) interactions between P-gp binding domains and inhibitors are dominant intermolecular forces that have been reported in many studies using different methods. Many synthetic and natural products have been found to possess inhibitory or modulatory effects on drug transporter proteins. Log P value is an important factor in studying these inhibitors and has a crucial role on absorption, distribution, metabolism, and excretion (ADME) properties of candidate P-gp inhibitors.

Topics: Acridines; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Binding Sites; Biological Products; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Lipid Bilayers; Molecular Targeted Therapy; Piperidines; Protein Conformation; Quinolines; Tetrahydroisoquinolines

Overexpression of P-glycoprotein (Pgp) increases multidrug resistance (MDR) in cancer, which greatly impedes satisfactory clinical treatment and outcomes of cancer patients. Due to unknown pharmacokinetics, the use of Pgp inhibitors to overcome MDR in the clinical setting remains elusive despite promising in vitro results. The purpose of our current preclinical study is to investigate the pharmacokinetics and tolerability of NSC23925b, a novel and potent P-glycoprotein inhibitor, in rodents. Plasma pharmacokinetic studies of single-dose NSC23925b alone or in combination with paclitaxel or doxorubicin were conducted in male BALB/c mice and Sprague-Dawley rats. Additionally, inhibition of human cytochrome P450 (CYP450) by NSC23925b was examined in vitro. Finally, the maximum tolerated dose (MTD) of NSC23925b was determined. NSC23925b displayed favorable pharmacokinetic profiles after intraperitoneal/intravenous (I.P./I.V.) injection alone or combined with chemotherapeutic drugs. The plasma pharmacokinetic characteristics of the chemotherapy drugs were not affected when co-administered with NSC23925b. All the animals tolerated the I.P./I.V. administration of NSC23925b. Moreover, the enzymatic activity of human CYP450 was not inhibited by NSC23925b. Our results demonstrated that Pgp inhibitor NSC23925b exhibits encouraging preclinical pharmacokinetic characteristics and limited toxicity in vivo. NSC23925b has the potential to treat cancer patients with MDR in the future.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 Enzyme System; Doxorubicin; Drug Evaluation, Preclinical; Humans; Inhibitory Concentration 50; Injections, Intraperitoneal; Injections, Intravenous; Isomerism; Male; Maximum Tolerated Dose; Mice; Mice, Inbred BALB C; Paclitaxel; Piperidines; Quinolines; Rats, Sprague-Dawley

The development of multidrug resistance (MDR) remains the significant clinical challenge in ovarian cancer therapy; however, relatively little is known about how to prevent the emergence of MDR during chemotherapy treatment. NSC23925 previously has been shown to prevent the development of MDR in osteosarcoma cells in vitro. The purpose of this study was to evaluate the effects of NSC23925 on the prevention of MDR in ovarian cancer, especially in vivo.. Human ovarian cancer cells were treated with paclitaxel alone or in combination with NSC23925 in vitro and in vivo. MDR ovarian cancer cells were established both in cultured cells and mouse models. The expression levels of Pgp and MDR1 were evaluated in various selected cell sublines by Western blot and real-time PCR. Pgp activity was also determined.. Paclitaxel treated cells eventually developed MDR with overexpression of Pgp and MDR1, and with high activity of Pgp, while paclitaxel-NSC23925 co-treated cells remained sensitive to chemotherapeutic agents in both in vitro and in vivo models. There was no observed increase in expression level and activity of Pgp in paclitaxel-NSC23925 co-treated cells. Additionally, there were no changes in the sensitivity to chemotherapeutic agents, nor expression of Pgp, in cells cultured with NSC23925.. Our findings suggest that NSC23925 can prevent the emergence of MDR in ovarian cancer both in vitro and in vivo. The clinical use of NSC2395 at the onset of chemotherapy may prevent the development of MDR and improve the clinical outcome of patients with ovarian cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Paclitaxel; Piperidines; Quinolines; Xenograft Model Antitumor Assays

Strategies to prevent the emergence of drug resistance will increase the effectiveness of chemotherapy treatment and prolong survival of women with ovarian cancer. The aim of our study is to determine the effects of NSC23925 on preventing the development of paclitaxel resistance in ovarian cancer both in cultured cells in vitro and in mouse xenograft models in vivo, and to further elucidate these underlying mechanisms. We first developed a paclitaxel-resistant ovarian cancer cell line, and demonstrated that NSC23925 could prevent the introduction of paclitaxel resistance by specifically inhibiting the overexpression of P-glycoprotein (Pgp) in vitro. The paclitaxel-resistant ovarian cancer cells were then established in a mouse model by continuous paclitaxel treatment in combination with or without NSC23925 administration in the mice. The majority of mice continuously treated with paclitaxel alone eventually developed paclitaxel resistance with overexpression of Pgp and antiapoptotic proteins, whereas mice remained sensitivity to paclitaxel and displayed lower expression levels of Pgp and antiapoptotic proteins after administered continuously with combination of paclitaxel-NSC23925. Paclitaxel-NSC23925-treated mice experienced significantly longer overall survival time than paclitaxel-treated mice. Furthermore, the combination of paclitaxel and NSC23925 therapy did not induce obvious toxicity as measured by mice body weight changes, blood cell counts and histology of internal organs. Collectively, our observations provide evidence that NSC23925 in combination with paclitaxel may prevent the onset of Pgp or antiapoptotic-mediated paclitaxel resistance, and improve the long-term clinical outcome in patients with ovarian cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Female; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Paclitaxel; Piperidines; Quinolines; Treatment Outcome; Xenograft Model Antitumor Assays

The major limitation to the success of chemotherapy in osteosarcoma is the development of multidrug resistance (MDR). Preventing the emergence of MDR during chemotherapy treatment has been a high priority of clinical and investigational oncology, but it remains an elusive goal. The NSC23925 has recently been identified as a novel and potent MDR reversal agent. However, whether NSC23925 can prevent the development of MDR in cancer is unknown. Therefore, this study aims to evaluate the effects of NSC23925 on prevention of the development of MDR in osteosarcoma.. Human osteosarcoma cell lines U-2OS and Saos were exposed to increasing concentrations of paclitaxel alone or in combination with NSC23925 for 6 months. Cell sublines selected at different time points were evaluated for their drug sensitivity, drug transporter P-glycoprotein (Pgp) expression and activity.. We observed that tumour cells selected with increasing concentrations of paclitaxel alone developed MDR with resistance to paclitaxel and other Pgp substrates, whereas cells cultured with paclitaxel-NSC23925 did not develop MDR and cells remained sensitive to chemotherapeutic agents. Paclitaxel-resistant cells showed high expression and activity of the Pgp, whereas paclitaxel-NSC23925-treated cells did not express Pgp. No changes in IC50 and Pgp expression and activity were observed in cells grown with the NSC23925 alone.. Our findings suggest that NSC23925 may prevent the development of MDR by specifically preventing the overexpression of Pgp. Given the significant incidence of MDR in osteosarcoma and the lack of effective agents for prevention of MDR, NSC23925 and derivatives hold the potential to improve the outcome of cancer patients with poor prognosis due to drug resistance.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bone Neoplasms; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Humans; Osteosarcoma; Paclitaxel; Piperidines; Quinolines

Development of multidrug resistance (MDR) during chemotherapy is a fundamental obstacle associated with cancer care. Prior studies have identified (2-(4-methoxyphenyl)-4-quinolinyl)(2-piperidinyl)methanol (5) (NSC23925) to be a small molecule agent that reverses MDR in cancer cells. We synthesized all four isomers of 5 and analyzed them by liquid chromatography-mass spectrometry (LCMS). Structure-activity relationships for reversing MDR were evaluated. Isomer 11 demonstrated the most potent activity. 11 reversed MDR in several drug-resistant cell lines expressing Pgp, including ovarian, breast, colon, uterine, and sarcoma cancer. 11 resensitized these cell lines to paclitaxel, doxorubicin, mitoxantrone, vincristine, and trabectedin with no effect on cell sensitivity to cisplatin, topotecan, and methotrexate. 11 significantly enhanced in vivo antitumor activity of paclitaxel in MDR xenograft models, without increasing the level of paclitaxel toxicity. In conclusion, 11 and derivatives of this compound may hold therapeutic value in the treatment of MDR-dependent cancers.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Crystallography, X-Ray; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Paclitaxel; Piperidines; Quinolines; Stereoisomerism; Structure-Activity Relationship; Transplantation, Heterologous

Multidrug resistance (MDR) is a major factor which contributes to the failure of cancer chemotherapy, and numerous efforts have been attempted to overcome MDR. To date, none of these attempts have yielded a tolerable and effective therapy to reverse MDR; thus, identification of new agents would be useful both clinically and scientifically.. To identify small molecule compounds that can reverse chemoresistance, we developed a 96-well plate high-throughput cell-based screening assay in a paclitaxel resistant ovarian cancer cell line. Coincubating cells with a sublethal concentration of paclitaxel in combination with each of 2,000 small molecule compounds from the National Cancer Institute Diversity Set Library, we identified a previously uncharacterized molecule, NSC23925, that inhibits Pgp1 and reverses MDR1 (Pgp1) but does not inhibit MRP or BCRP-mediated MDR. The cytotoxic activity of NSC23925 was further evaluated using a panel of cancer cell lines expressing Pgp1, MRP, and BCRP. We found that at a concentration of >10 microM NSC23925 moderately inhibits the proliferation of both sensitive and resistant cell lines with almost equal activity, but its inhibitory effect was not altered by co-incubation with the Pgp1 inhibitor, verapamil, suggesting that NSC23925 itself is not a substrate of Pgp1. Additionally, NSC23925 increases the intracellular accumulation of Pgp1 substrates: calcein AM, Rhodamine-123, paclitaxel, mitoxantrone, and doxorubicin. Interestingly, we further observed that, although NSC23925 directly inhibits the function of Pgp1 in a dose-dependent manner without altering the total expression level of Pgp1, NSC23925 actually stimulates ATPase activity of Pgp, a phenomenon seen in other Pgp inhibitors.. The ability of NSC23925 to restore sensitivity to the cytotoxic effects of chemotherapy or to prevent resistance could significantly benefit cancer patients.

Topics: Adenosine Triphosphatases; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Fluoresceins; Humans; Models, Chemical; Ovarian Neoplasms; Paclitaxel; Piperidines; Quinolines