“The protective effect of nano curcumin supplementation on doxorubicin induced cardiotoxicity in breast cancer patients;a randomized,double-blind clinical trial”

Abstract

Background

Anthracycline drugs play a fundamental role in breast cancer treatment; however, the cardiotoxicity side effects obscure the advantages of treatment. Curcumin has antioxidant and anti-inflammatory effects.

Materials and Methods

In this study, we investigated the effect of nanocurcumin supplementation on Doxorubicin induced Cardiotoxicity. In this randomized clinical trial, a week before starting the doxorubicin regimen for breast cancer patients, the control group received placebo and curcumin group received 80 mg daily dosage of nano curcumin capsules for six months. Echocardiography parameter changes before chemotherapy and after six months were evaluated.

Results

46 patients were included. Left ventricle (LV) ejection fraction significantly decreased and LV end diastolic volume significantly increased in control group but no significant changes were observed in the curcumin group (LVEF: 2.62 ± 59.35 to 4.23 ± 56.85, p-value: 0.014 vs 59.55 ± 1.91 to 58.46 ± 3.41, p-value:0.135; LVEDV: 77.09 ± 15.33 to 80.65 ± 14.54, p-value:0.023 vs 72.41 ± 15.34 74.00 ± 14.25, p-value: 0.294). Additionally, LVEF, LV end systolic diameter (LVESD), and end diastolic diameter (LVEDD) insignificantly more decreased in control group versus curcumin group (LVEF: 4.13 ± 2.50- vs 3.36 ± 1.08-, p-value: 0.223; LVESD: 0.27 ± 0.06-vs 0.120.45 ±, p-value:0.110; LVEDD: −0.44 ± 0.33 vs 0.070.33 ±, p-value:0.269). Furthermore, symptomatic cardiomyopathy and ejection fraction ratio less than 53% were not observed. The LVEF reduction >15% was observed was also high in the control group, (p-value = 0.020).

Conclusion

This study shows the possible effect of nanocurcumin capsules to reduce the cardiotoxicity of anthracycline chemotherapy medications.

Keywords

Breast cancer cardiotoxicity doxorubicin

Introduction

Increasing life expectancy of patients with tumors in recent years enable to identify more adverse effects of anti-tumor medications such as cardiotoxicity.¹ Doxorubicin is the most common widely used anti-tumor medication, however, cardiotoxicity which is already associated with cumulative dosage limited the potential benefits of this drug.^2–4 The underlying mechanism that prompts Doxorubicin induced cardiac toxicity (DIC) is oxidative stress and DNA repair impairment, and cellular senesces.⁵ Several strategies have been defined to reduce the risk of DIC including anthracycline combination therapy with natural antioxidants, cardioprotective medications^6,7 or pegylated nano liposome drug delivery.⁸ However, there is still no consensus on the reduction of DIC.

Among the natural agents, Curcumin has both anti-cancer and anti-inflammatory potential effects.^9,10 Curcumin downregulates the inflammasome and autophagosome to maintain cardiac function after Doxorubicin treatment.^11,12 Additionally, Curcumin has promising protective effects on the neurologic, nephrogenic, and hepatic cytotoxicity of chemotherapy drugs.¹³ Shati et al. found that Curcumin plus Doxorubicin reduces the concentration of Malondialdehyde and Tumor Necrosis Factor -α and increased the concentrations of superoxide dismutase and catalase.¹⁴ Additionally, curcumin was found with possible effect to decrease the DIC with reducing the iNOs, NF-κB, and TNF-α¹⁵ and prevents oxidative impairment and mitochondrial dysfunction in amelioration of DIC.¹⁶ Nevertheless, the water solubility, bioavailibity, rapid metabolism, and rapid clearance fails the biologic activity of Curcumin.¹⁷ In this regard, the nano-technology techniques utilized to overcome this problem preserving the anti-tumor activity and efficacy on the chemo-therapeutic adverse effects.¹⁸ Furthermore, previous studies have shown that nanoparticles of curcumin have a synergic effect by Doxorubicin¹⁹ and ameliorate DIC in in-vitro and in-vivo studies.^12,15,20,21 The Data of clinical studies are scant. In this study, we aimed to investigate the protective effects of curcumin nano-micelles against breast cancer patients’ cardiac toxicity induced by Doxorubicin.

Material and methods

Study population

This is a board review approved study conducted between 2018 and 2022 at two tertiary oncological hospitals. In the course of the study, initial visit was performed to check eligible patients according to the inclusion checklist, and the individuals interested in participating received relevant information about the study. If the individuals were suited for study participation, an appointment was made for medical screening. Patients were initially evaluated by physical examination performed by an investigator. Relevant laboratory and radiological tests were performed. When the inclusion criteria were met, the patients consented to participate in the study and underwent randomization. The sample size was estimated on the bases of a power (1 - β) of 80% and a significance level of .05 for a two-armed parallel study with two-tailed testing. Adhering to the minimum sample size of 14 in the study, 23 patients in each group were recruited in each group.

The target population for this study consisted of female patients aged 18–75 years with unilateral lesions without any metastases findings, for whom the immunohistochemistry showed A or B luminal, or triple-negative results in Chromogenic in-situ hybridization or Fluorescent in situ hybridization. All eligible patients who were candidates to receive doxorubicin had Karnofsky performance score (KPS) ≥ 60, an Eastern Cooperative Oncology Group (ECOG) score ≤2, and life expectancy ≥3 months. Radiographic evidence of the measurable disease was obtained 4 weeks before randomization. Patients who were pregnant or child-bearing, also had a history of previous chemotherapy and radiotherapy, dilated, restrictive, or hypertrophic cardiomyopathy. Patients with a history type of bundle branch block, coronary artery disease, any valvular diseases, any persistent arrhythmia, or a history of consumption of angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, beta-blockers, diuretics, calcium channel blocker, statins were excluded from the study (Figure 1).

Study design

The study was conducted as, randomized, double-blind, placebo-controlled, parallel-group, two-arm trial designed to investigate the efficacy and safety of Nano curcumin and Doxorubicin (curcumin group) in patients who received 80 mg of nano curcumin capsules (Sina Curcumin, Exir Nano Sina Company, Tehran, Iran) seven days before starting Doxorubicin regimen (60 mg/m², Four cycles) versus Doxorubicin; same regimen plus placebo (combination of Lecithin and E104 Yellow color) from the same company (placebo group) in the treatment of patients with breast cancer. The cause of non-simultaneous therapy or combination therapy is attributed to the accumulated dosage of curcumin and any adverse sensitivity.

Nano-micelle curcumin is prepared from generally recognized as a safe pharmaceutical excipients and C3-complex form of curcumin. 20 microliters of diluted nano-micelles curcumin were deposited onto the carbon-coated copper grid. The excess nano-micelles were removed by filter paper After 1 min, and stained with 20 μL of 1% sodium phosphotungstate (pH 7.0) for 2 min. Then, the excess stain was removed. The samples were viewed using a Phillips CM100 electron microscope. The percentage of encapsulation of Curcumin in this nano micelle is approximately 100% and its size is approximately 10 nm.²²

Randomization

The eligible patients were randomized 1:1 to one of the two study groups. The treatment agent was orally administered from one week before the start of chemotherapy until 24 weeks. At the first visit, each participant received a consecutive number ranging from 1 to 50. The participants were sequentially enrolled by the Principal Investigator and two medical oncologists. Each patient also assigned a random treatment code and received the package. Blinding off the trial subjects was performed using the labeled packages. The study medication was delivered to the clinic pre-labeled and coded according to the randomization list. The randomization code was kept secret from the clinic and the participating investigators and was only revealed after the termination of the study. The information related to the allocation of the participants was also kept in sequentially numbered and sealed envelopes that were stored by the director of the contract research organization. The individual treatment codes indicating treatment randomization for each randomized participant were available to the investigator.

Follow-up

The transthoracic echocardiographic (TTEC); two-dimensional, color-flow, spectral Doppler, and tissue Doppler imaging (TDI) using the Philips EPIQ CVx Cardiology Ultrasound System performed by a blinded Echocardiogram specialist in the echocardiography department according the criteria defined by American Society of Cardiology.²³ TTEC measurements were taken with patients in the left lateral decubitus position using standard parasternal long-axis and apical views. At least 3 consecutive beats were recorded, and the average values were obtained. The LVEDD and end-systolic dimensions (LVESD) were measured from M-mode recordings of the LV cavity with the cursor at the tip of the mitral valve leaflets in the parasternal long-axis view, and the LV ejection fraction (EF) was calculated by Simpsons method. Spectral Doppler velocities were measured in the apical four-chamber view using a 2-mm sample volume positioning at the mitral valve level. Peak early diastolic velocity (E-wave), peak atrial filling velocity (A-wave), E/A ratio, E-wave deceleration time, and isovolumic relaxation time (IVRT) were measured from Left Ventricle filling recordings. Early diastolic (Ea) and late diastolic (Aa) velocities were recorded from the velocity tracings.

Outcomes

The primary outcome of the study is the echocardiography parameter changes as the concern of DIC in both placebo and curcumin group in baseline and after 6-month of follow-up. The cut off of cardio toxicity is according to American society of Echocardiography (ASE and European association of cardiovascular imaging(EACVI): 1. ⩾10% decline in LVEF to a final value less than 53% confirmed on subsequent imaging performed 2 to 3 weeks after the initial measurement and or 2. >15% relative decline in global longitudinal strain (GLS) compared with baseline strain.²⁴ The secondary outcome is defined as the heart failure or any arrhythmia, cancer relapse, new cancer, valvular disease, and death.

Statistical analysis

Continuous variables were tested for normal distribution by the Kolmogorov– Smirnov test. We reported continuous data as mean ± standard deviation or median as appropriate. Continuous variables between groups were compared using the student t-test or Mann–Whitney U test, as appropriate. Categorical variables were summarized as percentages and compared using the Chi-square test. A paired t-test was used to investigate the time-dependent variables within patient groups. A two-sided p-value <0.05 was considered statistically significant. All statistical analyses were performed using the SPSS IBM version 21.

Results

Forty six consecutive patients were included in the study. 23 patients who received curcumin regimen and 23 patients who just received doxorubicin. The basal characteristics of patients demonstrated no differences between the two groups (Table 1).

Table 1.

Baseline characteristics of patients in two group.

Variables	ControlN = 23	CurcuminN = 23	p-value
Age	46.83 ± 8.03	43.20 ± 7.09	0.117
BMI (kg/m2)	26.51 ± 2.86	25.14 ± 4.10	0.508
BSA	1.75 ± 0.16	1.72 ± 0.13	0.718
Diagnosis interval	21.19 ± 12.73	31.75 ± 24.53	0.348
HR (beats/ min)	80.48 ± 16.57	80.25 ± 14.12	0.728
Smoking	0	1(4.33)	0.999
Diabetes	1(4.33)	0	0.999
HTN	1(4.33)	1(4.33)	0.999
Diastolic malfunction	2(8.67)	2(8.67)	0.999

Mean ± standard deviation, () percentage.

BMI, Body mass index; BSA, Body surface area; HR, Hear rate; HTN: hypertension.

The myocardial performance index changed significantly between baseline and 6-month follow-up (Table 2). Additionally, LVEDD and LVESD reduced in the placebo group, insignificantly (p-value: 0.537and 0.319), but in the curcumin group LVEDD and LVESD was insignificantly increased (p-value:0.347 and 0.206). The LVOT VTI and PVVTI significantly decreased in both group of study (p-value:0.039, 0.019 and 0.001,0.002). Additionally, MPI shows significant increase during follow-up (p-valu:0.022 and 0.030) (Table 2).

Table 2.

Comparison of electrocardiographic indexes in two group before and six- month follow up.

Variables	Control		p-value	Curcumin		p-value
Variables	Baseline	6-month	p-value	Baseline	6-month	p-value
Rate (MM)	16.57 ± 80.48	15.42 ± 82.52	0.266	14.12 ± 80.25	16.44 ± 79.60	0.776
BSA	0.16 ± 1.75	0.13 ± 1.76	0.329	0.13 ± 1.72	0.13 ± 1.71	0.137
LVEDD (mm)	0.33 ± 4.43	0.38 ± 4.39	0.537	0.26 ± 4.40	0.32 ± 4.47	0.347
LVESD (mm)	0.34 ± 2.74	0.34 ± 2.68	0.319	0.34 ± 2.63	0.43 ± 2.75	0.206
IVSD (mm)	0.10 ± 0.74	0.10 ± 0.71	0.061	0.08 ± 0.69	0.09 ± 0.68	0.539
LVEDV (ml)	15.33 ± 77.09	14.54 ± 80.65	0.023	15.34 ± 72.41	14.25 ± 74.00	0.294
LVEF (%)	2.62 ± 59.35	4.23 ± 56.85	0.014	1.91 ± 59.55	3.41 ± 58.46	0.135
Mid. RV (mm)	0.30 ± 2.62	0.31 ± 2.62	0.824	0.33 ± 2.59	±0.30 2.60	0.892
S (%)	1.63 ± 12.25	1.61 ± 12.12	0.426	1.61 ± 12.98	2.12 ± 13.11	0.548
LA area(cm³)	2.87 ± 16.02	3.07 ± 15.83	0.654	2.72 ± 15.01	2.74 ± 14.48	0.147
LA volume(cm³)	13.07 ± 44.87	13.19 ± 43.17	0.301	10.25 ± 39.73	11.05 ± 38.55	0.263
RA area(cm³)	1.90 ± 11.43	1.64 ± 11.27	0.168	2.25 ± 11.44	1.98 ± 11.26	0.333
RA volume(cm³)	5.99 ± 25.73	5.65 ± 25.41	0.329	7.96 ± 25.57	7.14 ± 25.30	0.654
Ao annulus (cm³)	0.10 ± 1.91	0.10 ± 1.91	0.970	0.18 ± 1.93	0.23 ± 1.91	0.517
SOV (cm/m²)	0.24 ± 2.85	0.23 ± 2.87	0.446	0.17 ± 2.77	0.24 ± 2.76	0.765
ASC (cm/m²)	0.33 ± 2.94	0.33 ± 2.95	0.815	0.27 ± 2.84	0.23 ± 2.84	0.789
Ao. PPG(cm²)	3.36 ± 7.50	2.28 ± 6.95	0.345	4.43 ± 8.30	1.58 ± 6.69	0.081
Ao. MPG(cm²)	1.68 ± 4.11	1.34 ± 4.09	0.934	1.20 ± 4.09	0.97 ± 3.70	0.059
AO. VTI (cm²)	5.91 ± 26.09	4.82 ± 24.54	0.173	4.07 ± 26.48	3.72 ± 23.69	0.001
	3.15 ± 19.23	3.21 ± 17.32	0.039	4.39 ± 20.00	2.91 ± 16.55	0.001
PV.PPG (cm²)	3.35 ± 5.00	2.15 ± 4.82	0.702	2.70 ± 4.78	2.01 ± 4.48	0.390
PV.MPG (cm²)	1.94 ± 2.64	0.86 ± 2.45	0.550	1.23 ± 2.61	0.94 ± 2.39	0.096
PV.VTI (cm²)	5.36 ± 20.73	4.90 ± 19.09	0.019	4.40 ± 21.22	3.19 ± 19.17	0.002
RVOTVTI (cm²)	3.74 ± 15.81	4.09 ± 14.95	0.254	2.69 ± 14.29	3.16 ± 13.39	0.030
PAP (mm Hg)	4.05 ± 23.58	3.82 ± 23.56	0.692	3.24 ± 23.80	2.96 ± 23.40	0.423
TV. Annulus(cm)	0.43 ± 2.65	0.41 ± 2.62	0.329	0.34 ± 2.68	0.43 ± 2.60	0.088
TRPG (mm Hg)	3.74 ± 19.00	2.78 ± 18.40	0.117	3.08 ± 18.81	2.63 ± 18.71	0.825
Sm (cm/sec)	1.22 ± 7.51	1.51 ± 7.39	0.654	16.63 ± 10.87	1.34 ± 7.50	0.338
Em (cm/sec)	2.63 ± 8.89	2.26 ± 8.36	0.160	2.34 ± 9.98	3.07 ± 9.10	0.156
Am(cm/sec)	1.68 ± 8.66	2.17 ± 9.11	0.088	1.87 ± 8.86	1.62 ± 8.96	0.695
E. EM (cm/sec)	11.45 ± 12.00	11.62 ± 11.43	0.233	1.50 ± 8.13	1.67 ± 8.55	0.271
E. velocity(cm/sec)	21.42 ± 72.72	14.16 ± 63.23	0.043	21.10 ± 69.69	11.88 ± 68.09	0.666
A. velocity(cm/sec)	22.68 ± 68.57	13.26 ± 71.95	0.391	19.87 ± 65.33	13.41 ± 69.04	0.230
DT (15)	41.14 ± 186.35	54.35 ± 196.65	0.313	39.16 ± 175.09	51.24 ± 192.90	0.084
IVRT (15)	16.97 ± 65.00	18.39 ± 63.90	0.755	20.76 ± 68.00	16.59 ± 59.50	0.059
MPI	0.15 ± 0.47	0.17 ± 0.57	0.022	0.17 ± 0.45	0.16 ± 0.55	0.030
S. D	1098 ± 57.05	9.78 ± 54.95	0.282	12.11 ± 53.61	14.96 ± 51.62	0.459

BSA, body surface area; LVEDD, left ventricular end diastolic dimension; LVESD, left ventricular end systolic dimension; IVSD, Intraventricular septum diameter; LVEF, left ventricular ejection fraction; mid RV, mid diameter of right ventricle; S, Tricuspid annular plane systolic excursion; LA, Left atrium; RA, right atrium; Ao, Aortic; PV, Pulmonary vein; PA, pulmonary artery; SOV, sinuses of Valsalva; ASC, ascending aorta; PPG, peak pressure gradient; MPG, mean pressure gradient; VTI, velocity time integral; PAP, pulmonary arterial pressure; TRPG, Tricuspid regurgitation peak gradient; E, peak early phase ﬁlling velocity; A, peak atrial phase ﬁlling velocity; Ea, early diastolic myocardial velocity; Aa, late diastolic myocardial velocity; Sa, systolic velocity; DT, deceleration time; IVRT, isovolumic relaxation time; MPI, myocardial performance index; LA /index, left atrium; EF %, ejection fraction; AR, atrial reversal; S/D, pulmonary vein peak systolic/peak diastolic velocity; Sm, peak systolic velocity of left ventricle; DT, Deceleration time of diastolic mitral flow.

EF reached less than 53% in none of the patients in the study. More than a 10% reduction in EF was observed in two patients (8.67%) in the curcumin group and four patients (17.35%) in the control group, with a p-value = 0.022 (Figure 2). There was also no significant reduction in LVEF between the two groups at baseline and 6-month follow-up (p-value = 0.223). In the control group, LVEF was significantly reduced after six months (p-value = 0.014) in comparison to the curcumin group (0.135) (Figure 3). Additionally, in the curcumin group, LVEDV was significantly reduced during follow-up (p-value = 0.023) compared with the control group (p-value = 0.294). There were no significant TTEC variable changes between the two groups; however, the curcumin group demonstrated slightly favorable results in comparison to the control group (Table 3). In conclusion, no significant difference in LVEDV between baseline and 6-month follow-up was also observed (Figure 4). According to our secondary outcomes, no mortality and arrhythmia were observed during 6-month follow-up study.

Table 3.

Echocardiographic index changes before and during six-month follow up.

	ControlN = 23	CurcuminN = 23	p-value
Rate (MM)	2.05 ± 8.20	−0.65 ± 10.06	0.351
LVEDD (mm)	−0.04 ± 0.33	0.07 ± 0.33	0.269
LVESD (mm)	−0.06 ± 0.27	0.12 ± 0.45	0.110
IVSD (mm)	−0.03 ± 0.07	−0.01 ± 0.07	0.347
LVEDV (ml)	−3.60 ± 7.00	−1.59 ± 6.93	0.348
LVEF (%)	−2.50 ± 4.13	−1.08 ± 3.36	0.223
Mid. RV (mm)	−0.004 ± 0.09	0.004 ± 0.15	0.816
S (%)	−0.13 ± 0.77	0.13 ± 1.02	0.335
LA area(cm³)	−0.19 ± 2.04	−0.53 ± 1.70	0.543
LA volume(cm³)	−1.70 ± 7.67	−1.18 ± 4.82	0.790
RA area(cm³)	−1.69 ± 7.68	−1.18 ± 4.82	0.789
RA volume(cm³)	−0.32 ± 1.49	−0.26 ± 2.75	0.932
Ao annulus (cm³)	−0.001 ± 0.06	−0.02 ± 0.13	0.567
SOV(cm/m²)	0.02 ± 0.11	−0.01 ± 0.14	0.475
ASC(cm/m²)	0.004 ± 0.09	0.004 ± 0.08	0.999
Ao.PPG(cm²)	−0.54 ± 2.65	−1.61 ± 4.20	0.318
Ao.MPG(cm²)	−0.02 ± 1.28	−0.39 ± 0.94	0.057
AO.VTI(cm²)	−1.54 ± 5.14	−2.78 ± 3.23	0.087
LVOT.VTI(cm²)	−1.91 ± 4.05	−3.57 ± 4.31	0.200
PV.PPG(cm²)	−0.18 ± 2.20	−0.30 ± 1.66	0.833
PV.MPG(cm²)	−0.18 ± 1.40	−0.22 ± 0.60	0.912
PV.VTI(cm²)	−1.63 ± 3.01	−2.04 ± 2.85	0.644
RVOT.VTI(cm²)	−0.85 ± 3.23	−0.89 ± 1.85	0.951
PAP(mm Hg)	−0.22 ± 2.34	−0.40 ± 2.18	0.810
TV. Annulus(cm)	−0.02 ± 0.11	−0.7 ± 0.20	0.290
TRPG(mm Hg)	−0.60 ± 1.63	−0.09 ± 1.95	0.375
Sm(cm/sec)	−0.13 ± 1.30	−3.37 ± 16.51	0.375
Em(cm/sec)	−0.59 ± 1.87	−0.88 ± 2.88	0.700
Am(cm/sec)	0.44 ± 104	0.10 ± 1.15	0.354
E. EM(cm/sec)	−0.57 ± 2.08	0.43 ± 1.68	0.062
E. velocity(cm/sec)	−9.49 ± 20.70	−1.60 ± 17.58	0.175
A. velocity(cm/sec)	3.38 ± 18.10	3.71 ± 14.41	0.947
DT (15)	10.30 ± 44.46	17.81 ± 46.10	0.594
IVRT (15)	−1.09 ± 15.87	−8.5 ± 18.86	0.181
MPI	0.09 ± 0.18	0.11 ± 0.21	0.850
S. D	−2.09 ± 8.45	−1.98 ± 11.76	0.974

LVEDD, left ventricular end diastolic dimension; LVESD, left ventricular end systolic dimension; IVSD, Intraventricular septum diameter; LVEF, left ventricular ejection fraction; mid RV, mid diameter of right ventricle; S, Tricuspid annular plane systolic excursion; LA, Left atrium; RA, right atrium; Ao, Aortic; PV, Pulmonary vein; PA, pulmonary artery; SOV, sinuses of Valsalva; ASC, ascending aorta; PPG, peak pressure gradient; MPG, mean pressure gradient; VTI, velocity time integral; PAP, pulmonary arterial pressure; TRPG, Tricuspid regurgitation peak gradient; E, peak early phase filling velocity; A, peak atrial phase filling velocity; Ea, early diastolic myocardial velocity; Aa, late diastolic myocardial velocity; Sa, systolic velocity; DT, deceleration time; IVRT, isovolumic relaxation time; MPI, myocardial performance index; LA /index, left atrium; EF %, ejection fraction; AR, atrial reversal; S/D, pulmonary vein peak systolic/peak diastolic velocity; Sm, peak systolic velocity of left ventricle; DT, Deceleration time of diastolic mitral flow.

Discussion

This study shows the possible effects of nano curcumin supplementation against DIC. LVEF significantly decreased in placebo group, but the LVEF reduction in curcumin group was insignificant. Additionally, LVEDV significantly increased in the placebo group, but the changes in curcumin group is not significant. Despite of insignificant findings between two groups, LVESD and LVEDD decreased in placebo group compared, but in curcumin group LVESD and LVEDD increased after 6-month follow-up. Additionally, all patients remained asymptomatic despite of a low EF ratio in TTEC. Furthermore, 15% reduction of EF in placebo group was higher than curcumin group. No patients were found with EF less than 50%.

In case of DIC reducing, nanostructures for delivery of therapeutic compounds not only increase anti-tumor function, but also obscure DIC.²⁵ Exosomes as new structures for delivery of therapeutics have been emerged that because they are isolated from the human cells, they have high biocompatibility that not only can ameliorate DIC through delivery of bioactive compounds, they can be utilized as diagnostic factors.²⁶ Recent studies have focused on the application of liposomes to reduce cardiotoxicity of drugs. A combination of lycopene liposomal nanostructures along with Doxorubicin can decrease cardiotoxicity.²⁷ The Doxorubicin-loaded liposomes display low systemic toxicity and in spite of increasing anti-cancer function, they significantly decrease DIC.²⁸ Additionally, co-delivering of paclitaxel and curcumin on polyethylene glycol-lactic acid-co-glycolic acid shows high tumor suppression and therapeutic outcomes in breast cancer patient.²⁹

Comparing with previous studies reported the reduction DIC following adjuvant therapy, nano curcumin capsules as an adjuvant of Doxorubicin shows promising results to lessen the risk of DIC. For instances, Kaya et al. in the 6-month follow-up clinical trial study of Nebivolol found that LVEF more decreased in Placebo versus Nebivolol group, however, LVESDD and LVEDD increased in the placebo group, while no changes were observed in the nebivolol group.³⁰ Nabati et al. in their randomized trial used carvedilol on 91 women with breast cancer found that LVEF was significantly reduced and LVESV and LA diameter were significantly increased compared with the baseline measures in the control group. Moreover, a significant decrease in the mitral annuli early diastolic and peak systolic velocities were also observed. However, none of these variables were adversely changed at the end of follow-up in the carvedilol group.³¹ Heck et al. in the two-years follow-up found that candesartan decreases LVEDV more than placebo, however, the LVEF reduction was not significantly differs with non-candesartan group.³² Another study included 83 patients with breast cancer found that insignificant LVEF reduction in the Spironolactone group is not significant compared with placebo group (p = 0.094 vs p < 0.001). Additionally, the diastolic functional grade of patients in control group deteriorated while no changes were observed in the spironolactone group(p-value < 0.001 vs p-value = 0.096).³³

According to other TTEC markers, LVOTVTI significantly decreased in both groups (Table 2). Although, LVOTVTI reduction was higher in curcumin group, the changes between the two groups were insignificant (p-value:0.200). LVOT VTI normal rang in healthy adult is between 15–29 cm.³⁴ LVOT VTI measurement correlates with indices of perfusion, and outperforms ejection fraction in patients with heart failure.³⁵ Additionally, Bonardeaux et al. found that LVOT VTI reduction shows sever cardiotoxicity of trastuzumab in patients with breast cancer.³⁶ Zhang et al. found significant reduction of LVOT VTI in patients received anthracyclines.³⁷ However, DIC with more than 15% reduction of EF was lower in the curcumin group. Moreover, curcumin also found with protective potential effects on the heart failure with several mechanisms.³⁸ It should also be noted that the MPI index is increased in both groups and highly amounts of changes were founded in curcumin group, but the changes remain insignificant between two groups. Previous studies found that higher Tei index associated to lower myocardial functions.³⁹ However, number of patients with 15% reduction of LVEF is markedly reduced study in the curcumin group. Against previous studies, Fernandes et al. represent the low correlation of MPI and cardiac dysfunction in patients with isolated diastolic dysfunctions.⁴⁰ On the hand, we only assessed the DIC by TTEC, our patients have not experienced any cardiac-related diseases. TTEC is a standard method for all patients with cancers who received Doxorubicin.⁴¹ In patients with a high volume reduction of ejection fraction, cardiac ischemia, or valvular disease, other diagnostic tools, including Cardiac Magnetic Resonance Imaging, Single Photon Emission Computed Tomography, and Stress Echocardiography may be helpful.⁴² A recent study on 33 patients with breast cancer who received anthracyclines, 2-dimensional speckle tracking echocardiography showed higher sensitivity to reveal LV functions against TTEC.⁴³

The developing risk of DIC is related to factors such as age, previous irradiation, and cumulative dosage of doxorubicin.⁴⁴ A cumulative dose of doxorubicin <300 mg / m² is safe, while the heart failure incidence increases at 7–25% for doses of 550 mg/m².⁴⁴ It should also be noted that with this regimen of doxorubicin administration in Breast Cancer patients, the risk of 5-year cardiotoxicity varies between 0 to1.6%.⁴⁵ A recent study on 910 patients found that the LVEF reduction after chemotherapy by anthracyclines is about 4.5%, and the most declination occurs in the first 6 months.⁴⁶ The evidence explains the effect of updated chemotherapy regimen and follow-up duration, and none of our patients’ EF ratios had reached less than 53%, respectively.

Our study also confirmed the recent findings of curcumin potential effects attenuating the DIC risk. Swamy et al. reported repeated oral administration of curcumin was then used as pretreatment for 2 weeks and for another 2 weeks in combination with Doxorubicin remarkably reduced DIC.⁴⁷ Benzer et al. found that Curcumin administration for rats by oral routine (100 or 200 mg/kg body weight) for 7 days could significantly enhanced the antioxidant markers activities due the DIC.⁴⁸ Moreover, previous in-vitro and in-vivo studies that demonstrated the effect of nanoparticle-based curcumin on the DIC.⁴⁹ Namdari et al. demonstrated that curcumin-loaded magnetic hydrogel nanocomposites reduced oxidative cascades in cardiomyocyte cell lines by reducing of malondialdehyde levels and increasing superoxide dismutase, and glutathione peroxidase enzymes.⁵⁰ Sharifi et al. demonstrated nanoparticle gold-coated curcumin reduced apoptotic proteins, such as Bax2 and caspase proteins, against increasing Bcl2 protein as an apoptotic protein on the first day and day fourteenth.²¹ Fouad et al. also demonstrated that prophylactic dosage of nanocurcumin reduces DIC by decreasing gamma interferon, and increasing iNOS, NF-kB, and Tissue necrotizing factor- α in mice models.¹⁵ In addition, nanoparticles of curcumin reduce cardiomyocyte edema and heart weight decreases following the Doxorubicin regimen.^51,52 Treatment of Wistar rat with curcumin-capped gold-loaded illustrated that cardiac anti-hypertrophy effect and enhanced cardiac systolic and diastolic function maintained heart weight and left ventricle pressure at the controlled level.⁵³ Nanocurcumin implicates anti-inflammatory responses, including c-reactive proteins and interleukin 6, and regulating the serum lipids as risk factors for cardiovascular diseases.⁵⁴

The limitation of this study is the measurement of curcumin plasma levels in our patients. The cumulative dosage of nanocurcumin supplementation and effect of long-term consumption outcome and the patient compliance of supplementation compliance is still unknown. Additionally, the single blinded Echocardiologic would affect our results. So, future studies would be designated to ensure the TTEC indices changes adhering to LVEF, LVEDV, LVESD, LVEDD, and other cardiography markers.

Conclusion

This study shows cardioprotective effect of curcumin nanoparticles in breast cancer patients who receive Doxorubicin. Larger clinical trials with long-term follow-up could evaluate the result of nano herbal medication in the field of anthracyclines induce cardiac toxicity.

Footnotes

Acknowledgment

The authors would like to express their gratitude to all the study participants for their corporations. The work was supported by Research project No.961246 as a thesis, financed by Mashhad University of Medical Sciences, Mashhad, Iran. We would also like to thanks the clinical Research Development Center, Ghaem Hospital, Mashhad University of Medical Sciences for their assistance in the manuscript.

Authors' contributions

Mehdi Tohidi: Writing original draft, Investigation

Abolghasem Allahyari: Conceptualization, Methodology, Supervision

Sajad Ataei Azimi: Conceptualization, Methodology

Sepideh Elyasi: Investigation

Hedieh Alimi: Investigation, Data curation

Farid Qoorchi Moheb Seraj: Writing original draft, Investigation, Formal analysis

Hasan Mehrad-Majd: Conceptualization, Formal analysis, Interpretation, writing review and editing, Project administration

Data availability

The data will be available by the corresponding author at reasonable request.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval

The clinical trial was registered in the Irania Clinical trial registry site, Health government () on and 2/27/2019. The approval code is IRCT20190224042818N1. The informed consent was obtained from the patients or their first-grade relatives. The ethical committee of the Mashhad University of Medical Sciences approved the study (IR.MUMS.MEDICAL.REC.1397.503).

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Sepideh Elyasi

Farid Qoorchi Moheb Seraj

References

Spetz

Moslehi

Sarosiek

. Radiation-induced cardiovascular toxicity: mechanisms, prevention, and treatment. Curr Treat Options Cardiovasc Med 2018; 20: 1–11.

Dulf

Mocan

Coadă

, et al. Doxorubicin-induced acute cardiotoxicity is associated with increased oxidative stress, autophagy, and inflammation in a murine model. Naunyn Schmiedebergs Arch Pharmacol 2023; 396: 1–11.

Swain

Whaley

Ewer

. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003; 97: 2869–2879.

Ewer

Lippman

. "Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity" by Michael. J Clin Oncol 2005; 23: 2900–2902.

Rawat

Jaiswal

Khurana

, et al. Doxorubicin-induced cardiotoxicity: an update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother 2021; 139: 111708.

Fabiani

Aimo

Grigoratos

, et al. Oxidative stress and inflammation: determinants of anthracycline cardiotoxicity and possible therapeutic targets. Heart Fail Rev 2021; 26: 881–890.

Mir

Badi

Bugazia

, et al. Efficacy and safety of cardioprotective drugs in chemotherapy-induced cardiotoxicity: an updated systematic review & network meta-analysis. Cardiooncology 2023; 9: 1–34.

Xing

Yan

, et al. Efficacy and cardiotoxicity of liposomal doxorubicin-based chemotherapy in advanced breast cancer: a meta-analysis of ten randomized controlled trials. PLoS One 2015; 10: e0133569.

Aggarwal

Kumar

Bharti

. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 2003; 23: 363–398.

10.

Mohajeri

Sahebkar

. Protective effects of curcumin against doxorubicin-induced toxicity and resistance: a review. Crit Rev Oncol Hematol 2018; 122: 30–51.

11.

Man

Karki

Briard

, et al. Differential roles of caspase-1 and caspase-11 in infection and inflammation. Sci Rep 2017; 7: 45126.

12.

Qin

Zhang

, et al. Curcumin suppresses doxorubicin-induced cardiomyocyte pyroptosis via a PI3 K/Akt/mTOR-dependent manner. Cardiovasc Diagn Ther 2020; 10: 752–769.

13.

Liu

Huang

Law

, et al. Preventive effect of curcumin against chemotherapy-induced side-effects. Front Pharmacol 2018; 9: 1374.

14.

Shati

Eid

El-kott

, et al. Curcumin attenuates doxorubicin-induced cardiotoxicity via suppressing oxidative Stress, preventing inflammation and apoptosis: Ultrastructural and computational approaches. Heliyon 2024; 10: e27164.

15.

Fouad

Ahmed

. Curcumin ameliorates doxorubicin-induced cardiotoxicity and hepatotoxicity via suppressing oxidative stress and modulating iNOS, NF-κB, and TNF-α in rats. Cardiovasc Toxicol 2022; 22: 152–166.

16.

Luo

Qiao

, et al. Curcumin attenuates doxorubicin-induced cardiotoxicity via suppressing oxidative stress and preventing mitochondrial dysfunction mediated by 14–3-3γ. Food Funct 2018; 9: 4404–4418.

17.

Perrone

Ardito

Giannatempo

, et al. Biological and therapeutic activities, and anticancer properties of curcumin. Exp Ther Med 2015; 10: 1615–1623.

18.

Hafez Ghoran

Calcaterra

Abbasi

, et al. Curcumin-based nanoformulations: a promising adjuvant towards cancer treatment. Molecules 2022; 27: 5236.

19.

Mahjoub

Bakhshinejad

Sadeghizadeh

, et al. Combination treatment with dendrosomal nanocurcumin and doxorubicin improves anticancer effects on breast cancer cells through modulating CXCR4/NF-κB/Smo regulatory network. Mol Biol Rep 2017; 44: 341–351.

20.

Mohammed

Hosny

Khadrawy

, et al. Protective effect of curcumin nanoparticles against cardiotoxicity induced by doxorubicin in rat. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2020; 1866: 165665.

21.

Sharifiaghdam

Dalouchi

Sharifiaghdam

, et al. Curcumin-coated gold nanoparticles attenuate doxorubicin-induced cardiotoxicity via regulating apoptosis in a mouse model. Clin Exp Pharmacol Physiol 2022; 49: 70–83.

22.

Rahimi

Nedaeinia

Shamloo

, et al. Novel delivery system for natural products: nano-curcumin formulations. Avicenna J Phytomed 2016; 6: 383.

23.

Mitchell

Rahko

Blauwet

, et al. Guidelines for performing a comprehensive transthoracic echocardiographic examination in adults: recommendations from the American society of echocardiography. J Am Soc Echocardiogr 2019; 32: 1–64.

24.

Plana

Galderisi

Barac

, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American society of echocardiography and the European association of cardiovascular imaging. Eur Heart J Cardiovasc Imaging 2014; 15: 1063–1093.

25.

Gou

Gao

HJN

. Doxorubicin nanomedicine based on ginsenoside Rg1 with alleviated cardiotoxicity and enhanced antitumor activity. Nanomedicine (Lond) 2021; 16: 2587–2604.

26.

Tian

Yang

Bai

, et al. Potential of exosomes as diagnostic biomarkers and therapeutic carriers for doxorubicin-induced cardiotoxicity. Int J Biol Sci 2021; 17: 1328.

27.

Zhu

Shen

. Enhanced antitumor efficacy and attenuated cardiotoxicity of doxorubicin in combination with lycopene liposomes. J Liposome Res 2020; 30: 37–44.

28.

Chen

, et al. Quick-responsive polymer-based thermosensitive liposomes for controlled doxorubicin release and chemotherapy. ACS Biomater Sci Eng 2019; 5: 2316–2329.

29.

Lin

Wang

, et al. Nanoparticles for co-delivery of paclitaxel and curcumin to overcome chemoresistance against breast cancer. Oncotarget 2023; 79: 104050.

30.

Kaya

Ozkan

Gunebakmaz

, et al. Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study. Int J Cardiol 2013; 167: 2306–2310.

31.

Nabati

Janbabai

Baghyari

, et al. Cardioprotective effects of carvedilol in inhibiting doxorubicin-induced cardiotoxicity. J Cardiovasc Pharmacol 2017; 69: 279–285.

32.

Heck

Mecinaj

Ree

, et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): extended follow-up of a 2× 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Circulation 2021; 143: 2431–2440.

33.

Akpek

Ozdogru

Sahin

, et al. Protective effects of spironolactone against anthracycline-induced cardiomyopathy. Eur J Heart Fail 2015; 17: 81–89.

34.

Evangelista

García del Castillo

González-Alujas

, et al. Normal values of valvular flow velocities determined by Doppler echocardiography: relations with heart rate and age. Rev Esp Cardiol 1996; 49: 189–195.

35.

Omote

Nagai

Iwano

, et al. Left ventricular outflow tract velocity time integral in hospitalized heart failure with preserved ejection fraction. ESC heart Failure 2020; 7: 167–175.

36.

de la Brassinne Bonardeaux

Born

Moonen

, et al. Mild cardiotoxicity and continued trastuzumab treatment in the context of HER2-positive breast cancer. J Clin Med 2023; 12: 6708.

37.

Zhang

Azibani

Libhaber

, et al. Detecting subclinical anthracycline therapy-related cardiac dysfunction in patients attending Uganda cancer institute. Future Oncology (London, England) 2022; 18: 2675–2685.

38.

Pourbagher-Shahri

Farkhondeh

Ashrafizadeh

, et al. Curcumin and cardiovascular diseases: focus on cellular targets and cascades. Biomed Pharmacother 2021; 136: 111214.

39.

Askin

Yuce

Tanriverdi

. Myocardial performance index and cardiovascular diseases. Echocardiography (Mount Kisco, NY) 2023; 40: 720–725.

40.

Fernandes

JMG

de Oliveira Romão

Rivera

, et al. Clinical value of myocardial performance index in patients with isolated diastolic dysfunction. Cardiovasc Ultrasound 2019; 17: 17.

41.

Anqi

Mingjun

, et al. Use of echocardiography to monitor myocardial damage during anthracycline chemotherapy. Echocardiography 2019; 36: 495–502.

42.

Kim

Chung

W-B

Cho

, et al. Diagnosis, treatment, and prevention of cardiovascular toxicity related to anti-cancer treatment in clinical practice: an opinion paper from the working group on cardio-oncology of the Korean society of echocardiography. Journal of Cardiovascular Ultrasound 2018; 26: 1–25.

43.

Chen

Jiao

, et al. Two-dimensional speckle tracking echocardiography, a powerful method for the evaluation of anthracyclines induced left ventricular insufficiency. Medicine (Baltimore) 2022; 101: e31084.

44.

Saleh

Abdelkarim

Herzallah

, et al. Anthracycline-induced cardiotoxicity: mechanisms of action, incidence, risk factors, prevention, and treatment. Heart Fail Rev 2021; 26: 1159–1173.

45.

Trudeau

Charbonneau

Gelmon

, et al. Selection of adjuvant chemotherapy for treatment of node-positive breast cancer. Lancet Oncol 2005; 6: 886–898.

46.

Lee

ARYB

Yau

Low

, et al. Natural progression of left ventricular function following anthracyclines without cardioprotective therapy: a systematic review and meta-analysis. Cancers (Basel) 2023; 15: 512.

47.

Swamy

Gulliaya

Thippeswamy

, et al. Cardioprotective effect of curcumin against doxorubicin-induced myocardial toxicity in albino rats. Indian J Pharmacol 2012; 44: 73–77.

48.

Benzer

Kandemir

Ozkaraca

, et al. Curcumin ameliorates doxorubicin-induced cardiotoxicity by abrogation of inflammation, apoptosis, oxidative DNA damage, and protein oxidation in rats. J Biochem Mol Toxicol 2018; 32: e22030.

49.

Moutabian

Ghahramani-Asl

Mortezazadeh

, et al. The cardioprotective effects of nano-curcumin against doxorubicin-induced cardiotoxicity: a systematic review. Biofactors 2022; 48: 597–610.

50.

Namdari

Eatemadi

. Cardioprotective effects of curcumin-loaded magnetic hydrogel nanocomposite (nanocurcumin) against doxorubicin-induced cardiac toxicity in rat cardiomyocyte cell lines. Artif Cells Nanomed Biotechnol 2017; 45: 731–739.

51.

Guo

, et al. Co-assembly of doxorubicin and curcumin targeted micelles for synergistic delivery and improving anti-tumor efficacy. Eur J Pharm Biopharm 2017; 112: 209–223.

52.

Peng

Fumoto

Miyamoto

, et al. One-step formation of lipid-polyacrylic acid-calcium carbonate nanoparticles for co-delivery of doxorubicin and curcumin. J Drug Target 2017; 25: 704–714.

53.

Liu

, et al. In vivo evaluation of enhanced drug carrier efficiency and cardiac anti-hypertrophy therapeutic potential of nano-curcumin encapsulated photo-plasmonic nanoparticles combined polymerized nano-vesicles: a novel strategy. J Photochem Photobiol B 2019; 199: 111619.

54.

Ashtary-Larky

Kelishadi

Bagheri

, et al. The effects of nano-curcumin supplementation on risk factors for cardiovascular disease: a GRADE-assessed systematic review and meta-analysis of clinical trials. Antioxidants (Basel) 2021; 10: 1015.