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Hier het commentaar van arts-bioloog drs. Engelbert Valstar op onderstaande studiepublicatie:
29 maart 2019: Aanvullend commentaar:
Curcumine met peper verlaagt tamoxifenspiegel iets. Curcumine alleen niet aantoonbaar. Het bewijst dus dat zwarte peper de tamoxifenspiegel verlaagt. Los van dat er geen placebocorrectie is, is de hoofdconclusie fout. Dit is wel een enorme blunder: het onderzoek zegt dus zelf niets ten nadele van curcumine. Ze hadden een groep met alleen zwarte peper mee moeten nemen.
Als we de Bonferroni-correctie in maximale gestrengheid hier toepassen: tamoxifen en een metaboliet op 2 momenten na t=0, met en zonder piperine dan zijn er 8 'vergelijkingen'; de significantiegrens ligt dan bij 0,05/8= < 0,007 ; elke significantie verdwijnt dan
Kees, mijn voorlopige commentaar: De spiegels van tamoxifen en een metaboliet zijn lager met curcumine en piperine, maar niet aantoonbaar met curcumine alleen. Omdat er naar meerdere variabelen is gekeken en het aantal patienten klein is, is de significantie met curcumine en piperine veel geringer dan gesuggereerd. Voorts betreft het een zeer hoge dosis. Drie keer 1200 mg curcumine : 3600 mg zit normaliter in let wel 72 gram curcumapoeder. Daarbij komt dat er niet naar een biologische eindmaat is gekeken, bijvoorbeeld het aantal tumorregressies bij gebruik van tamoxifen met/zonder curcumine etc. Verder is er van placebocorrectie geen sprake. Daarbij komt verder dat modelmatig onderzoek laat zien dat curcumine de gevoeligheid van borstkankercellen voor tamoxifen kan vergroten (PMID 23299550) Mijn conclusie is dat het onderzoek geen harde conclusies over een mogelijke interactie toelaat. Mijn ervaring is dat als er een interactie ongunstig is, er 19 gunstige tegenover staan. Een expliciet ongunstige is er bijvoorbeeld tussen vitamine C en Velcade. Niet voor niets heb ik per cytostaticum, maar ook bij bestraling rijtjes gunstige en ongunstige interacties.
27 maart 2019: Bron: AD en Cancers2019, 11(3), 403; doi: 10.3390/cancers11030403
Onderzoekers van het Erasmus MC komen vandaag met een waarschuwing tegen kurkuma gebruik (curcumine) naast hromoontherapie (Tamoxifen) door borstkankerpatiënten. Zij krijgen van het Algemeen Dagblad alle ruimte om hun bevindingen uit een bloedwaardenstudie met 16 borstkankerpatiënten (!!!!) breed uit te meten en voor het gebruik van curcumine - kurkuma supplementen te waarschuwen. (Zoals ze eerder deden voorSt. Janskruid).
Echter de onderzoekers vonden alleen dat er bij een paar patiënten in het bloed minder van de werkzame stof uit Tamoxifen en Endoxifen aanwezig was en ook 7 procent tot 12 procent (met zwarte peper) van de curcumine (Redactie: blijkbaar wordt curcumine dus wel degelijk opgenomen in het bloed in tegenspraak dus met wat dr. Timmermans beweert, maar dit terzijde) De onderzoekers hebben echter niet getest of kunnen constateren dat de patienten ook daadwerkelijk minder reageerden op de verandering in de bloedwaarden.
Gezien alle onderstaande informatie is de boodschap van de onderzoekers van het Erasmus echt paniekzaaien om niets naar mijn mening. Zie ook reactie van arts-bioloog drs. Engelbert Valstar bovenaan dit artikel
Een deel van de conclusie: Although, the interaction term was only significant for tamoxifen AUC0–24h and Ctrough with curcumin and piperine. There was no period effect, which implicated no decline in tamoxifen nor endoxifen plasma concentrations based on altered tamoxifen metabolism over time. Individual tamoxifen and endoxifen AUC0–24h can be found in Figure 2 and in Supplementary Figure S1.
Figure 2. Endoxifen and tamoxifen AUC0–24h per individual patient per treatment phase: (a) Tamoxifen AUC0–24h per individual patients per treatment phase. (b) endoxifen AUC0–24h per individual patients per treatment phase. Patients with an intermediate CYP2D6 metabolism (IM) were colored blue. Patients with an extensive CYP2D6 metabolism (EM) were colored black. Poor CYP2D6 metabolizers (PM) and ultra-rapid CYP2D6 metabolizers (UR) were colored green and red, respectively; *: decrease in AUC0–24h >25%; a total of four patients showed a >25% decrease in endoxifen AUC0–24h and three patients in tamoxifen AUC0–24h when tamoxifen was administered with curcumin and piperine, compared to tamoxifen monotherapy.
In een andere laboratoriumstudie blijkt namelijk juist wel dat curcumine - kurkuma juist de werking van tamoxifen versterkt:
die aantoont dat curcumine wel degelijk effect heeft op bepaalde mutaties in de P53, (ca. 50 procent van alle kankerpatienten met een recidief en / of uitzaaiingen hebben een afwijking in het P53 gebied) Het voorkomt en herstelt bepaalde vorming van essentiële mutaties (Uit de conclusie: The numerous health benefits of curcumin, its cost-effectiveness, and its ability to target multiple components in BC make it an ideal agent for further development to produce more effective therapies against BC.)
Uit het abstract:
Curcumin is a natural product, extracted from the roots of Curcuma longa, and possesses various biological effects including anticancer activity. Previous studies proved the ability of curcumin to modulate several signaling pathways and biomolecules in cancer. Safety and cost-effectiveness are additional inevitable advantages of curcumin. This review summarizes the effects of curcumin as a regulator of p53 in BC and the key molecular mechanisms of this regulation.
Nog een citaat uit dit studierapport:
Curcumin can induce apoptosis in a p53- independent manner, especially in cancer cells that lack a functional p53 protein by downregulating pro-survival protein (Bcl-2) and p38 MAPK.118,119 This dietary natural compound inhibits the p300-mediated acylation of p53 that interacts with the p300/CBP complex to enhance its transcriptional effect.120 Additionally, other molecular targets for curcumin were reported in several studies testing its anticancer effect against breast cancer.121–125Figure 3 summarizes the main regulatory points of curcumin in BC. In addition, in vitro studies on various BC cell lines in addition to a brief summary about the inhibitory effects of curcumin in animal models are listed in Tables 1 and and2,2, respectively.
Ook Michal Heger (AMC) heeft ook wel kritiek op de uitlatingen van zijn collega's in het Erasmus MC in het Algemeen Dagblad artikel:
Uit het AD artikel: Michal Heger deed jarenlang onderzoek naar curcumine, de werkzame stof uit kurkuma, bij het AMC. Hij noemt de studie van zijn Rotterdamse collega’s ‘een superbelangrijke vinding’. Toch vraagt hij om de specerij nu niet af te doen als ‘totaal waardeloos’. Curcumine kan volgens hem bij enkele andere kankersoorten de chemotherapie wél gunstig beïnvloeden. ,,Curcumine werkt niet genezend bij kanker. Dat is een doodzieke kankerpatiënt valse hoop geven, maar het kan bij verschillende kankersoorten ook de bijwerkingen van de chemo verzachten. Denk aan misselijkheid en pijn.”
Onder borstkankerpatiënten leeft het idee dat kurkuma kanker kan bestrijden. Maar pas op, zeggen onderzoekers van het Erasmus MC na een nieuwe studie. Deze specerij tast de werking van een veelgebruikt kankermedicijn aan.
Hanneke van Houwelingen
Het is een hype die al jaren hardnekkig standhoudt: de specerij kurkuma (geelwortel) die in de Aziatische keuken wordt gebruikt zou een geneeskrachtige werking hebben op kanker. Curcumine, de werkzame stof uit kurkuma, zou in staat zijn om kankercellen op te ruimen. Bewijs hiervoor werd in dierproeven gevonden.
Reden voor veel borstkankerpatiënten om extra veel van dit gele poeder over hun eten te strooien of capsules met kurkuma te slikken. ,,Veel patiënten redeneren: als je het ook kunt eten in een curry, kan het geen kwaad. Als het dan ook helpt tegen kanker, is dat mooi meegenomen. Maar daar komen wij van terug. Doe het niet”, waarschuwt arts-onderzoeker Koen Hussaarts van het Erasmus MC.>>>>>>lees verder het hele artikel
Hier het abstract plus referentielijst van deze studie:
In conclusion, the exposure to tamoxifen and endoxifen was significantly decreased by concomitant use of curcumin (+/− piperine). Therefore, co-treatment with curcumin could lower endoxifen concentrations below the threshold for efficacy (potentially 20–40% of the patients), especially in EM patients.
Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
2
Department of Internal Medicine, Elisabeth Tweesteden Hospital, Hilvarenbeekseweg 60, 5022 GC Tilburg, The Netherlands
3
Department of Internal Medicine, Alrijne Hospital, Simon Smitweg 1, 2353 GA Leiderdorp, The Netherlands
4
Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Kleiweg 500, 3045 PM Rotterdam, The Netherlands
5
Department of Clinical Chemistry, Erasmus MC, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
6
Department of Hospital Pharmacy, Erasmus MC, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Received: 14 February 2019 / Accepted: 18 March 2019 / Published: 22 March 2019
Abstract
:
Tamoxifen is a prodrug that is primarily metabolized into the pharmacologically active metabolite endoxifen and eventually into inactive metabolites. The herb curcumin may increase endoxifen exposure by affecting phase II metabolism. We compared endoxifen and tamoxifen exposure in breast cancer patients with or without curcumin, and with addition of the bio-enhancer piperine. Tamoxifen (20–30mg per day (q.d.)) was either given alone, or combined with curcumin (1200 mg three times daily (t.i.d.)) +/− piperine (10 mg t.i.d.). The primary endpoint of this study was the difference in geometric means for the area under the curve (AUC) of endoxifen. Genotyping was performed to determine CYP2D6 and CYP3A4 phenotypes. The endoxifen AUC0–24h decreased with 7.7% (95%CI: −15.4 to 0.7%; p = 0.07) with curcumin and 12.4% (95%CI: −21.9 to −1.9%; p = 0.02) with curcumin and piperine, compared to tamoxifen alone. Tamoxifen AUC0–24h showed similar results. For patients with an extensive CYP2D6 metabolism phenotype (EM), effects were more pronounced than for intermediate CYP2D6 metabolizers (IMs). In conclusion, the exposure to tamoxifen and endoxifen was significantly decreased by concomitant use of curcumin (+/− piperine). Therefore, co-treatment with curcumin could lower endoxifen concentrations below the threshold for efficacy (potentially 20–40% of the patients), especially in EM patients.
Supplementary Materials
The following are available online at https://www.mdpi.com/2072-6694/11/3/403/s1, Figure S1: Time-concentration (AUC) curves for both tamoxifen (A) and endoxifen (B) for every individual patient (coded as patient 001–016).
Author Contributions
Conceptualization: R.H.J.M., K.G.A.M.H., R.W.F.v.L., A.J., E.O.-d.H., and T.v.G.; Data curation K.G.A.M.H., D.P.H., and E.O.-d.H.; Formal analysis: K.G.A.M.H., E.O.-d.H., and D.P.H. Funding acquisition: R.H.J.M., R.W.F.v.L., and D.P.H.; Investigation: K.G.A.M.H., D.P.H., L.J.v.H., S.B., M.B.V., A.J., R.H.J.M., R.J.v.A., L.E.A.S., Q.C.v.R.-S., and R.H.N.v.S.; Methodology: E.O.-d.H.; Project administration: K.G.A.M.H.; Resources: R.H.J.M. and R.H.N.v.S.; Supervision: R.H.J.M.; T.v.G., and R.W.F.v.L.; Writing—original research: D.P.H., K.G.A.M.H., R.W.F.v.L., R.H.J.M., and T.v.G.; Writing—review & editing: E.O.-d.H., A.J., L.v.H., S.B., M.B.V., R.J.v.A., L.E.A.S.; Q.C.v.R.-S., and R.H.N.v.S.
Funding
This research was funded by the Coolsingel Foundation (grant number: 553).
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. This work was presented as a proffered paper at the 54th ASCO annual meeting (4 June 2018, Chicago, IL, USA, abstract number: 2572).
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Figure 1.The major primary metabolite N-desmethyl-tamoxifen and the minor primary metabolite 4-hydroxytamoxifen are formed by N-demethylation and 4-hydroxylation of tamoxifen, through CYP3A4 and CYP2D6 metabolism, respectively. Further CYP-mediated metabolism of these metabolites results in the formation of 4-hydroxy-N-desmetyltamoxifen (endoxifen). Endoxifen is ultimately metabolized through phase II metabolism into among others endoxifen–glucoronide through UDP-glucuronyltransferases (UGTs) and also through sulfotransferase (SULT) enzymes.
Figure 2.Endoxifen and tamoxifen AUC0–24h per individual patient per treatment phase: (a) Tamoxifen AUC0–24h per individual patients per treatment phase. (b) endoxifen AUC0–24h per individual patients per treatment phase. Patients with an intermediate CYP2D6 metabolism (IM) were colored blue. Patients with an extensive CYP2D6 metabolism (EM) were colored black. Poor CYP2D6 metabolizers (PM) and ultra-rapid CYP2D6 metabolizers (UR) were colored green and red, respectively; *: decrease in AUC0–24h >25%; a total of four patients showed a >25% decrease in endoxifen AUC0–24h and three patients in tamoxifen AUC0–24h when tamoxifen was administered with curcumin and piperine, compared to tamoxifen monotherapy.
Table 1.Patient characteristics.
Characteristic
N (%)
Patients
16 (100)
Randomization sequence
- ABC
9 (56)
- CBA
7 (44)
Adjuvant tamoxifen treatment
16 (100)
Age (Median, IQR)
45 (42–58)
Sex
- Female
15 (94)
- Male
1 (6)
Race
- Caucasian
15 (94)
- Arabic
1 (6)
Height (Median, IQR)
171 (167–176)
Weight (Median, IQR)
73 (65–91)
BMI (Median, IQR)
25 (23–29)
WHO Performance Status
- 0
13 (81)
- 1
3 (19)
Previous chemotherapy
- Yes
12 (75)
○ TAC
2 (13)
○ AC - paclitaxel
4 (25)
○ FEC - docetaxel
6 (37)
- No
4 (25)
Previous RTx
- Yes
10 (63)
- No
6 (37)
Tamoxifen dose
- 20 mg
15 (94)
- 30 mg
1 (6)
Genotype
- CYP3A4*22
○ EM
16 (100)
- CYP2D6
○ EM
7 (44)
○ IM
7 (44)
○ PM
1 (6)
○ UM
1 (6)
Abbreviations: IQR = interquartile range; TAC = Docetaxel, doxorubicin, and cyclofosfamide; AC = doxorubicin and cyclofosfamide; FEC = 5FU, epirubicine, and cyclofosfamide; RTx = radiotherapy; EM = extensive metabolism phenotype; IM = intermediate metabolism phenotype; PM = poor metabolism phenotype; UM = ultra-rapid metabolism phenotype.
Table 2.Tamoxifen pharmacokinetics.
PK Parameters
Tamoxifen Monotherapy (A)
Tamoxifen + Curcumin (B)
Tamoxifen + Curcumin + Piperine (C)
Relative Difference A vs B (95%CI)
p-Value
Relative Difference (A vs C) (95%CI)
p-Value
Tamoxifen
AUC0–24h
5951 (20)
5460 (24)
5171 (23)
−8.0% (−14.1 to −1.4)
0.02
−12.8% (−19.2 to −5.9)
<0.01
Ctrough
213 (27)
198 (28)
187 (24)
−7.1% (−17.1 to +4.0)
0.25
−12.2% (−21.5 to −1.8)
0.02
Cmax
356 (16)
324 (21)
313 (22)
−8.4% (−16.4 to +0.5)
0.07
−11.1% (−18.1 to −3.6)
<0.01
Tmax
2.4 (1.9 to 3.1)
2.4 (1.9 to 3.0)
2.7 (1.9 to 3.8)
0.74
0.34
Endoxifen
AUC0–24h
597 (59)
556 (52)
518 (54)
−7.7 % (−15.4 to +0.7)
0.07
−12.4% (−21.9 to −1.9)
0.02
Ctrough
25 (60)
23 (53)
21 (55)
−5.6 % (−15.6 to +5.5)
0.43
−12.4% (−20.9 to −3.0)
0.01
Cmax
31 (56)
28 (50)
27 (51)
−7.1% (−16.3 to +3.2)
0.20
−9.8% (−20.1 to +1.8)
0.10
Tmax
2.0 (1.3 to 3.0)
1.7 (1.2 to 2.6)
1.8 (1.1 to 3.1)
0.88
0.62
4-hydroxy-tamoxifen
AUC0–24h
113 (31)
106 (24)
103 (28)
−6.3 % (−11.6 to −0.73)
0.03
−8.2% (−17.0 to +1.6)
0.11
Ctrough
4.4 (34)
4.2 (26)
4.1 (28)
−4.3 % (−12.3 to +4.4)
0.45
−7.3 (−17.6 to +4.3)
0.26
Cmax
6.0 (32)
5.4 (26)
5.4 (31)
−10.0% (−16.8 to −2.6)
<0.01
−8.8% (−20.0 to +4.0)
0.20
Tmax
2.7 (1.9 to 3.9)
2.4 (1.8 to 3.3)
2.8 (2.0 to 3.8)
0.42
0.37
N-desmethyl-tamoxifen
AUC0–24h
11596 (21)
10766 (24)
10084 (31)
−7.0% (−13.1 to −0.6)
0.03
−12.4% (−22.3 to −1.3)
0.03
Ctrough
463 (28)
430 (29)
411 (32)
−7.2% (−15.0 to +1.2)
0.10
−10.9% (−21.6 to +1.3)
0.08
Cmax
602 (21)
556 (24)
540 (32)
−7.2% (−14.9 to +1.1)
0.09
−9.7% (−20.2 to +2.3)
0.12
Tmax
2.6 (1.8 to 3.7)
1.7 (1.2 to 2.4)
2.1 (1.4 to 3.2)
0.24
0.88
Abbreviations: PK = pharmacokinetics; CI = Confidence Interval; AUC0–24h= area under the curve, timepoint 0 h to 24 h (expressed as geomean nM·h/mL (CV%)); Ctrough= minimum concentration (expressed as geomean nM/mL (CV%)); Cmax= maximum concentration (expressed as geomean nM/mL (CV%)); Tmax= time until maximum concentration (expressed as median h (IQR)); CV% = coefficient of variation; IQR = interquartile range.
Table 3.Tamoxifen pharmacokinetics, based on CYP2D6 phenotype.
PK Parameters
Tamoxifen Monotherapy (A)
Tamoxifen + Curcumin (B)
Tamoxifen + Curcumin + Piperine (C)
Relative Difference A vs B (95%CI)
p-Value
Relative Difference A vs C (95%CI)
p-Value
Intermediate Metabolizers (IM)
Tamoxifen AUC0–24h
5795 (4895–6859)
5427 (4313–6830)
5518 (4679–6508)
−7.2% (−18.2 to +5.4)
0.19
−5.3% (−13.1 to +3.1)
0.16 *
Tamoxifen Ctrough
200 (160–251)
191 (146–249)
199 (167–237)
−5.9% (−20.9to +11.9)
0.41
−1.3% (−15.3 to 15.1)
0.84 *
Endoxifen AUC0–24h
523 (362–755)
472 (339–656)
477 (340–669)
−9.4% (−21.7 to +4.8)
0.14
−10.3% (−23.5 to 5.3)
0.14
Endoxifen Ctrough
21 (14–32)
19 (13–27)
19 (14–27)
−10.7% (−28.2 to 11.2)
0.24
−8.3% (−27.2 to 15.4)
0.38
Extensive Metabolizers (EM)
Tamoxifen AUC0–24h
6077 (4882–7565)
5471 (4247–7047)
4836 (3720–6288)
−10.3% (−19.7 to +0.3)
0.06
−22.0% (−29.0 to −4.2)
<0.01 *
Tamoxifen Ctrough
218 (163–291)
199 (148–268)
170 (132–218)
−9.6% (−26.4 to +11.2)
0.27
−24.6% (−33.9 to −14.1)
<0.01 *
Endoxifen AUC0–24h
745 (576–963)
716 (574–893)
596 (495–717)
−5.7% (−19.6 to +10.7)
0.39
−18.4% (−36.1 to +4.3)
0.09
Endoxifen Ctrough
30 (23–39)
31 (25–38)
25 (20–30)
−0.3% (−12.8 to +13.9)
0.96
−17.2% (−26.1 to −7.3)
<0.01 *
Abbreviations: PK = pharmacokinetics; CI = Confidence Interval; AUC0–24h= Area under the curve, timepoint 0 h to 24 h (expressed as geomean nM·h/mL (95%CI)); Ctrough= minimum concentration (expressed as geomean nM/mL (95%CI)); * Interaction term reached statistical significance (p < 0.05).
Table 4.Adverse Events.
Adverse Event
Tamoxifen Monotherapy N (%) (A)
Tamoxifen with Curcumin N (%) (B)
Tamoxifen with Curcumin and Piperine N (%) (C)
Nausea
2(13)
1(6)
1(6)
Diarrhea
0
1(6)
3(19)
Constipation
2(13)
4(25)
1(6)
Fatigue
2(13)
3(19)
3(19)
Hot flashes
3(19)
5(31)
4(25)
Reflux
1(6)
1(6)
0
Dyspnea
0
1(6)
0
Anorexia
1(6)
0
1(6)
Pain
4(25)
0
2(13)
Rash
1(6)
0
1(6)
Hypophosphatemia
0
0
1(6)
Hyperlipidemia
1(6)
1(6)
1(6)
Legend: Number of patients with all Common Terminology Criteria for Adverse Events (CTCAE)-grade adverse events when treated with tamoxifen with or without curcumin and piperine expressed as number of patients (% of total number of patients).
Many animal and clinical studies supported the use of curcumin to treat different cancer types including BC. Curcumin can be considered for further testing to augment conventional anticancer therapies. However, the low bioavailability of this phytochemical is one of the main problems to be solved before using it as a standard therapeutic agent to treat cancer.
p53 is a tumor suppressor gene involved in various cellular mechanisms including DNA repair, apoptosis, and cell cycle arrest. More than 50% of human cancers have a mutated nonfunctional p53. Breast cancer (BC) is one of the main causes of cancer-related deaths among females. p53 mutations in BC are associated with low survival rates and more resistance to the conventional therapies. Thus, targeting p53 activity was suggested as an important strategy in cancer therapy. During the past decades, cancer research was focused on the development of monotargeted anticancer therapies. However, the development of drug resistance by modulation of genes, proteins, and pathways was the main hindrance to the success of such therapies. Curcumin is a natural product, extracted from the roots of Curcuma longa, and possesses various biological effects including anticancer activity. Previous studies proved the ability of curcumin to modulate several signaling pathways and biomolecules in cancer. Safety and cost-effectiveness are additional inevitable advantages of curcumin. This review summarizes the effects of curcumin as a regulator of p53 in BC and the key molecular mechanisms of this regulation.
Disclosure
The authors report no conflicts of interest in this work.
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