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Phenothiazines have been used in many areas of medicine, mainly in psychopharmacology. These compounds are able to effectively inhibit dopamine, histamine, serotonin, acetylcholine, and α-adrenergic receptors; thus, their effect and side-effect profiles are extremely diverse. Besides their antipsychotic activity, phenothiazines have a significant antimicrobial effect as well, since they can enhance the bactericidal function of macrophages and inhibit efflux pumps. They are also able to eliminate bacterial resistance plasmids and destroy bacteria by their membrane-destabilizing effect. Their antiviral, antiprotozoal, antifungal, and antiprion activities have also been described. Phenothiazines have also been proven to destroy cancer cells and sensitize them to chemotherapy. Anti-angiogenesis and anticancer stem cell activities have also been reported, and they might be applied as adjuvants in the treatment of infections and tumors in the future. Finally, phenothiazines can also be effective in the treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Efflux pump inhibitors are attractive compounds that reverse multidrug resistance (MDR) in cancer cells. In the present study, 10 phosphorus ylides (P-ylides) were compared based on their MDR-reverting activity in human ATP-binding cassette sub-family B member 1 (ABCB1; P-glycoprotein) gene-transfected L5178Y mouse T-lymphoma cells. Among them, three P-ylides, Ph3P=C(COCF3)COPh, Ph3P=C(COC2F5)COPh and Ph3P=C(COC3F7)COPh were identified as selectively modulating the ABCB1 pump. These compounds, with low cytotoxicity against mouse T-lymphoma cells, exhibited more potency than the positive control ABCB1 inhibitor verapamil., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: The most common mechanism that reduces the efficacy of anticancer agents is overexpression of ATP-binding cassette (ABC) drug transporters. Phenothiazines and structurally-related compounds can sensitize multidrug-resistant (MDR) cells to chemotherapeutics., Materials and Methods: Phenothiazine derivatives were investigated regarding their anticancer and MDR-reversing effect on colonic adenocarcinoma cells. The anti-proliferative and cytotoxic effects of the derivatives were assessed by the thiazolyl blue tetrazolium bromide (MTT) method, the modulation of the ABCB1 activity was measured by rhodamine 123 accumulation assay using flow cytometry., Results: All phenothiazines exhibited potent cytotoxic effect on the sensitive and MDR colon adenocarcinoma cell lines. The inhibition of the ABCB1 transporter was greater in the presence of the phenothiazine derivatives than for the known ABCB1 inhibitor verapamil., Conclusion: It can be concluded that these derivatives show synergism in the presence of doxorubicin and could have potential as ABCB1 inhibitors., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Resistance to chemotherapy is a main problem in cancer. The search for new effective compounds that can increase sensitivity of resistant cells to existing chemotherapeutics is an urgent need. In previous studies, it has been demonstrated that steroid derivatives showed promising results concerning their capacity to modulate resistance of multidrug-resistant cell lines., Materials and Methods: Steroid derivatives were studied for their growth-inhibitory effect, cytotoxicity, reversal of multidrug resistance, apoptosis induction, and interaction with doxorubicin on multidrug resistant human ATP-binding cassette, sub-family B, member 1 (ABCB1) gene-transfected mouse T-lymphoma cell line, and human PC-3 and LNCaP prostate cancer cell lines in vitro. The steroidal interaction with P-glycoprotein (ABCB1) was investigated by molecular docking., Results: Both the activity of steroid derivatives on inhibition of the ABCB1 pump and their interaction with doxorubicin are dependent on the substituent groups of the investigated steroidal structures. Even though the investigated steroid derivatives were found to have limited antiproliferative effect on the three different cancer cell lines, in combination with doxorubicin, most of them acted as good potentiators. The binding energies from molecular docking ranged from -6.43 to -9.88 kcal/mol. The predicted inhibition constants ranged from 0.1 to 10.1 μM. A significant negative correlation was found between binding energy and fluorescence activity ratio (R=-0.5, p=0.015)., Conclusion: The effective compounds can be candidates of model molecules for possible application in the treatment of multidrug resistant cancer in rational drug design., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Phenothiazines have anticancer properties and are able to reverse the multidrug resistance of neoplastic cells by inhibiting the ATP-binding cassette, sub-family B (MDR/TAP), member 1 protein (ABCB1 or P-glycoprotein) activity., Materials and Methods: A series of new phenothiazine derivatives was investigated regarding their ABCB1-modulating effect on multidrug resistant mouse T-lymphoma cells by rhodamine 123 accumulation assay and real-time ethidium bromide accumulation assay., Results: The phenothiazine derivatives exhibited a potent anticancer effect on the parental cell line and on its multidrug-resistant mouse T-lymphoma subline overexpressing the ABCB1 transporter. The inhibition of the ABCB1 transporter in the presence of the newly-developed phenothiazines was greater than that for the known ABCB1 inhibitors thioridazine and verapamil., Conclusion: Based on the chemical structures and biological activity, compounds with bivalent sulfur atom in the phenothiazine ring demonstrated marked ABCB1-modulating effect, however, other derivatives with halogen or amide substitutions were ineffective.

Bacteria and cancer cells frequently increase their resistance to chemotherapeutics as a consequence of therapy. Whenever studied, refractory response to chemotherapy is due to the over-expression of efflux pumps that render the bacterium or cancer cell resistant not only to the agent used for therapy, but to many, if not all other agents as well. Control over the efflux pump that bestows multidrug resistance has been a goal of research during the past decade. As a consequence of this search for inhibitors of efflux pumps, it has been noted that many agents which affect the efflux pump system of bacteria also have similar activity against efflux pumps of drug-resistant cancer cells. This review aims to identify such agents.

Aim: Chlorpromazine has activity against a large variety of cancer types. However, this phenothiazine produces a plethora of serious side-effects. We have studied thioridazine (TZ), a phenothiazine neuroleptic that is much milder, for activity against multidrug-resistant (MDR) cancer cells, as well as against the overexpressed ABCB1 transporter (P-glycoprotein) that is the cause for the MDR phenotype of these cancer cells., Materials and Methods: MDR mouse T-lymphoma cells, transfected with the human gene ABCB1 that codes for the transporter ABCB1, were incubated with TZ for various periods of time and examined for evidence of apoptosis. Concentrations of TZ were evaluated for activity against the ABCB1 transporter with the aid of an automated ethidium bromide (EB) method., Results: TZ induces apoptosis of MDR cancer cell line, as well as inhibits the activity of the overexpressed ABCB1 transporter of these cells., Conclusion: Because thioridazine has been in moderately safe use for over 40 years for the therapy of psychosis, it has the potential to serve as an adjuvant with anticancer agents, rendering the a priori MDR cancer cells susceptible to the anticancer agent.

Background: Hydantoin derivatives are very promising candidates to improve the efficacy of anticancer chemotherapy. Previously, we demonstrated that eight hydantoin derivatives inhibited the P-glycoprotein (ABCB1) efflux pump of mouse T-lymphoma cells, as well as acting synergistically with the anticancer drug doxorubicin., Materials and Methods: The activity of the hydantoin derivatives were investigated in another MDR cancer model, namely Colo 205/S sensitive and Colo 320/R resistant colon carcinoma cells respectively, having normal or overexpressed ABCB1 systems., Results: Among the hydantoin derivatives evaluated, BS-1, MN-3 and JH-63 were the most effective ABCB1 transporter inhibitors at the concentration of 4 mg/l on the Colo 320/R cells, compared to the positive control, verapamil., Conclusion: The derivatives did not induce apoptosis of Colo 320/R resistant colon carcinoma cells, indicating that these hydantoin compounds are potent efflux pump inhibitors (EPI) without affecting the signalling pathways that regulate apoptosis.

Background: Hydantoin derivatives possess a variety of biochemical and pharmacological properties. Although hydantoin compounds are studied extensively, there are not many studies that investigate their anticancer properties., Materials and Methods: Thirty hydantoin compounds were evaluated for their efflux modulating effects in cancer cells using a rhodamine 123 accumulation assay and real-time fluorometry based on the intracellular accumulation of ethidium bromide., Results: The 30 derivatives were screened by real-time fluorometry for rhodamine 123 accumulation. Among the selected derivatives, compounds SZ-7, LL-9, BS-1, MN-3, P3, RW-15b, AD-26, RW-13, AD-29 and KF-2 significantly increased the retention of rhodamine 123. Compounds AD-26, AD-29, RW-13, KF-2, BS-1, MN-3, RW-15b and JH-63 showed synergistic effect with doxorubicin on mouse lymphoma cells. Furthermore, compound SZ-7 had indifferent effect with doxorubicin., Conclusion: These results indicated the role of chemical modifications within the hydantoin ring for its potential inhibition of the ABCB1 transporter. The most active structures contained aromatic substituents as well as some tertiary amine fragments.

Background: Cancer cells become refractory to chemotherapy as a consequence of their overexpressing ABC transporters that extrude not only the therapeutic agent but other unrelated compounds such as chemotoxins and biocides before they can reach their intended targets. A compound that can inhibit the activity of these transporters may find use as an adjunct to chemotherapy that had been rendered ineffective., Materials and Methods: Four curcubitane-type triterpenes isolated from Momordica balsamina Linn. (Cucurbitaceae), a plant from Mozambique were evaluated for their inhibition of the ABC transporter P-glycoprotein coded by the human ABCB1 gene transfected into mouse lymphoma cells. The evaluation was conducted by flow cytometry using rhodamine 123 and real-time fluorometry assessing accumulation of ethidium bromide (EB) on a real-time basis., Results: Among the compounds isolated, the most active was 7-methoxycucurbita-5,24-diene-3beta,23(R)-diol, which inhibited the efflux of ethidium bromide (EB) and rhodamine 123 from the ABCB1-transfected mouse lymphoma cell., Conclusion: Real-time fluorometry replicated the flow cytometric results with significant advantages for the evaluation of efflux pump inhibitors. The substitution of side groups on the cucurbitane skeleton appears to be significant in the inhibition of ABCB1 activity.

Background: We have developed a semi-automated fluorometric method that utilizes ethidium bromide (EB), a common substrate of bacterial efflux pumps. The method is sufficiently sensitive to characterize the efflux pump systems of bacteria. Because EB is also recognized and extruded by ATP-binding cassette (ABC) transporters and these have similarity to P-glycoprotein (P-gp), the method has been extended for the evaluation of agents that can inhibit the extrusion of EB on a real-time basis by mouse lymphoma cells containing the human ABCB1 (mdr1) gene., Materials and Methods: Monitoring of uptake and extrusion of EB was assessed using the Rotor-Gene 3000 (Corbett Research) under different conditions., Results: Whereas extrusion of EB took place readily, the addition of known inhibitors of efflux pumps (verapamil, reserpine) caused retention of EB., Conclusion: This method is inexpensive and allows the detection of neoplastic cells with increased efflux activity as well as the screening of large numbers of compounds for inhibition of the P-gp.

The ability of fifteen cycloartanes, isolated from Euphorbia species, to reverse multidrug resistance (MDR) and apoptosis induction in L5178Y mouse lymphoma cells, including its multidrug-resistant subline, was studied by flow cytometry. Reversion of MDR was investigated using a standard functional assay with rhodamine 123 as a fluorescent substrate analogue. For the evaluation of apoptosis, the cells were stained with FITC-labeled annexin V and propidium iodide. The majority of the compounds were able to reverse MDR of the tested human MDR1 gene-transfected mouse lymphoma cells. Some of the compounds were able to induce moderate apoptosis in the PAR cell line, but this effect was less effective on multidrug-resistant cells. The results indicate that cycloartanes can be substrates of ABC transporters, which might compete with certain anticancer chemotherapeutics.