Drug resistance in multiple myeloma: cyclosporin A analogues and their metabolites as potential chemosensitizers

Pilarski, LM; Rw, Yatscoff; Murphy, Gardner; Belch, AR

doi:10.1038/sj.leu.2400984

Cited by 13 publications

(6 citation statements)

References 17 publications

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“…For example, the inhibition of the mammalian target of rapaymycin/Akt pathway has been associated with an anti-tumor effect in MM cells treated with pomalidomide [41]. Mycophenolate mofetil has an anti-proliferative effect on MM in vitro [42], and cyclosporine may sensitize MMs tumoral cells to chemotherapy in vitro [43]. Nevertheless, these results are not sufficient to form a conclusion about the effects of immunosuppressive therapy on PCN in vivo in KT.…”

Section: Discussionmentioning

confidence: 99%

Plasma cell neoplasia after kidney transplantation: French cohort series and review of the literature

et al. 2017

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Although post-transplant lymphoproliferative disorder (PTLD) is the second most common type of cancer in kidney transplantation (KT), plasma cell neoplasia (PCN) occurs only rarely after KT, and little is known about its characteristics and evolution. We included twenty-two cases of post-transplant PCN occurring between 1991 and 2013. These included 12 symptomatic multiple myeloma, eight indolent myeloma and two plasmacytomas. The median age at diagnosis was 56.5 years and the median onset after transplantation was 66.7 months (2–252). Four of the eight indolent myelomas evolved into symptomatic myeloma after a median time of 33 months (6–72). PCN-related kidney graft dysfunction was observed in nine patients, including six cast nephropathies, two light chain deposition disease and one amyloidosis. Serum creatinine was higher at the time of PCN diagnosis than before, increasing from 135.7 (±71.6) to 195.9 (±123.7) μmol/l (p = 0.008). Following transplantation, the annual rate of bacterial infections was significantly higher after the diagnosis of PCN, increasing from 0.16 (±0.37) to 1.09 (±1.30) (p = 0.0005). No difference was found regarding viral infections before and after PCN. Acute rejection risk was decreased after the diagnosis of PCN (36% before versus 0% after, p = 0.004), suggesting a decreased allogeneic response. Thirteen patients (59%) died, including twelve directly related to the hematologic disease. Median graft and patient survival was 31.7 and 49.4 months, respectively. PCN after KT occurs in younger patients compared to the general population, shares the same clinical characteristics, but is associated with frequent bacterial infections and relapses of the hematologic disease that severely impact the survival of grafts and patients.

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Section: Discussionmentioning

confidence: 99%

Plasma cell neoplasia after kidney transplantation: French cohort series and review of the literature

et al. 2017

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“…Obviously, MDR 1 is only one of several mechanisms through which myeloma patients may become refractory to chemotherapy (Gieseler & Nussler, 1998;Raaijmakers et al, 1998;Sonneveld, 1999). The question remains whether a benefit by MDR 1 reversal may be expected early during the disease, when the frequency of MDR 1 and other resistance pathways may still be low, as opposed to highly refractory patients who have no other treatment options left (Futscher et al, 1996;Pilarski et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC–HOVON randomized phase III study (06914)

et al. 2001

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Summary. Patients with multiple myeloma (MM) refractory to alkylating agents frequently express P-glycoprotein (Pgp), which is associated with the multidrug resistance (MDR) phenotype. We have conducted a randomized phase II/III study of the MDR reversal agent cyclosporin A combined with VAD (vincristine, doxorubicin, dexamethasone) compared with standard VAD in patients with MM stage IIA/IIIA who were refractory to or progressive after treatment with alkylating agents. Out of 81 patients who were randomized, 75 were eligible and evaluable: 34 in the VAD 1 cyclosporin A arm versus 41 in the VAD arm. Toxicities of grade 2±3 were observed more often with VAD 1 cyclosporin A than with VAD only: nausea (30% versus 8%, P 0´015), mucositis (18% versus 5%, P 0´13), infection (45% versus 35%, P 0´50). The treatment results were similar in the two arms: 53% versus 49% responded [95% CI (218´5%, 26´9%)]. The median progression-free survival (PFS) was 8´6 months (VAD 1 cyclosporin A) versus 5´8 months (VAD): [log rank P 0´16, hazard ratio 0´71, 95% CI (0´44, 1´15)], and median overall survival was 13 months versus 14´6 months [log rank P 0´89, hazard ratio 0´96, 95% CI (0´62, 1´72)]. The cause of death was progressive disease (85%), toxicity (10%) or other (5%). Bone marrow analysis performed in 23 patients showed that the response rate was 67% in Pgppositive versus 55% in Pgp-negative patients. Cyclosporin A combined with VAD is relatively well tolerated. There is no effect of cyclosporin A on the overall response rate, PFS and overall survival with VAD.

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“…Using intracellular accumulation of calcein, daunorubicin and vincristine as a marker for P-gp inhibition, we screened more than 800 plant extracts that are available in Korea and China and selected 8 for further investigation: Aloe ferox, Caesalpinia sappon, Dalbergia odorifera, Curcuma zedoariae rhizome, Zanthoxylum planisinum, Ageratum conyzoides, Curcuma aromatica and Culcuma longa. We also examined the effect of 3 herbal constituents, curcumin, quercetin and flavones, which are abundant in the extracts (Pilarski et al, 1998) and are reported to inhibit P-gp (Choi et al, 2004a;Choi et al, 2004b;Shin et al, 2006;Limtrakul, 2007;Pilarski et al, 1998). Since calcein, daunorubicin and vincristine, P-gp substrates used in the present study, are also substrates for MRP1 (Essodaigui et al, 1998;Renes et al, 1999;Versantvoort et al, 1994), the involvement of endogenous transporters (e.g.…”

Section: Discussionmentioning

confidence: 97%

Screening for Chemosensitizers from Natural Plant Extracts through the Inhibition Mechanism of P-glycoprotein

Ahn¹,

Song²

2010

Journal of Pharmaceutical Investigation

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P-gp plays a critical role in drug disposition and represents a mechanism for the development of multidrug resistance. Flavonoids, a major class of natural compounds widely present in foods and herbal products, have been shown to inhibit P-gp. Therefore, the aim of this study was to identify new candidate chemosensitizers by screening various plant extracts. The ability of natural plant extracts to inhibit P-gp activity was assessed by measuring cellular accumulation of calcein AM, daunorubicin and vincristine in P-gp overexpressing MDCKII-MDR1 cells. Among more than 800 plant extracts, eight were found to inhibit P-gp activity. Curcuma aromatica extract produced greatest inhibition, followed by Curcuma longa and Dalbergia odorifera extracts. Extracts of Aloe ferox, Curcuma zedoariae rhizome, Zanthoxylum planispinum, and Ageratum conyzoides showed moderate inhibitory effects. Curcumin and quercetin exhibited similar inhibition of P-gpmediated efflux of daunorubicin and vincristine, and flavones had a lesser effect. When chemosensitizing effect was evaluated by measuring daunorubicin sensitivity to MDCKII-MDR1 cells in the presence of natural plant extracts, Curcuma aromatica showed the most potent chemosensitizing effect based on daunorubicin cytotoxicity. In conclusion, natural plant extracts such as Curcuma aromatica can potently inhibit P-gp activity and may have potential as a novel chemosensitizers.

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Drug resistance in multiple myeloma: cyclosporin A analogues and their metabolites as potential chemosensitizers

Cited by 13 publications

References 17 publications

Plasma cell neoplasia after kidney transplantation: French cohort series and review of the literature

Plasma cell neoplasia after kidney transplantation: French cohort series and review of the literature

Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC–HOVON randomized phase III study (06914)

Screening for Chemosensitizers from Natural Plant Extracts through the Inhibition Mechanism of P-glycoprotein

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