Journal of Cancer Research and Therapeutics

ORIGINAL ARTICLE
Year
: 2018  |  Volume : 14  |  Issue : 12  |  Page : 1183--1187

Influence of pharmorubicin on the left ventricular ejection fraction of patients with breast cancer: A mechanism study


Hu Liu1, Ming-rui Xie2, Hui Gao3, Jian Li4,  
1 Xi'an JiaoTong University, Xi'an; Cardiovascular Center, Affiliated Hospital of Yan'an University, Yan'an, ShaanXi, China
2 Department of Oncology, Yulin Second Hospital, Yulin, ShaanXi, China
3 Department of Radiology, Affiliated Hospital Yan'an University, Yan'an, ShaanXi, China
4 Department of Gland Vascular Surgery, Affiliated Hospital of Yan'an University, Yan'an, ShaanXi, China

Correspondence Address:
Jian Li
Department of Gland Vascular Surgery, Affiliated Hospital of Yan'an University, No. 43 North Street, Yan'an 716000, ShaanXi
China

Abstract

Aims: Breast cancer is a great public health problem. It remains unclear how pharmorubicin induces cardiac dysfunction in patients with breast cancer. Our study was aimed to explore the influence of pharmorubicin on the left ventricular ejection fraction (EF) of patients with breast cancer and its potential mechanism. Materials and Methods: Patients with breast cancer were enrolled at the same hospital. Group I consisted of 135 samples, who were under treatment of pharmorubicin (200 mg/m2). Group II consisted of 144 samples, who were under treatment the of pharmorubicin (360 mg/m2). Group III was used as control group, which consists of 120 samples without treatment of pharmorubicin. Color Doppler ultrasonic inspection and measurement were performed to examine EF. Flow cytometry was performed to assess oxygen free radical level in hemocytes. Further combination therapy (N-acetylcysteine [NAC] + pharmorubicin) was provided for patients, and the same examinations were performed for the assessment of cardiac function and oxygen free radical level. Results: The ultrasound results showed that pharmorubicin treatment significantly jeopardized cardiac function, verified by decrease of both EF and fractional shortening (FS) (P < 0. 05). Moreover, such effect was dose-dependent. Oxygen free radical level was remarkably increased after pharmorubicin treatment (P < 0. 05), verified by flow cytometry. Adjunctive therapy of NAC decreased oxygen free radical level and improved cardiac function of patients with breast cancer, suggesting NAC ameliorated side effect of pharmorubicin treatment. Conclusions: Pharmorubicin treatment decreased EF and FS of patients with breast cancer through increasing oxygen free radical level in hemocytes. Adjunctive therapy of NAC could be a potential treatment to ameliorated side effect pharmorubicin treatment.



How to cite this article:
Liu H, Xie Mr, Gao H, Li J. Influence of pharmorubicin on the left ventricular ejection fraction of patients with breast cancer: A mechanism study.J Can Res Ther 2018;14:1183-1187


How to cite this URL:
Liu H, Xie Mr, Gao H, Li J. Influence of pharmorubicin on the left ventricular ejection fraction of patients with breast cancer: A mechanism study. J Can Res Ther [serial online] 2018 [cited 2019 Oct 18 ];14:1183-1187
Available from: http://www.cancerjournal.net/text.asp?2018/14/12/1183/247189


Full Text



 Introduction



As the main type of cancer occurring in female patients, breast cancer is a global public problem which puts greats threat on female health.[1],[2] Mortality of breast cancer presents a descend trend due to scientific and technological progress.[3],[4] To be specific, early screening of breast cancer increases sensitivity and accuracy of early diagnosis, and comprehensive therapy of breast cancer improves efficacy.[5],[6] Therapeutic methods of breast cancer include surgical treatment, chemical treatment, drug treatment, and molecular targeting treatment whereas chemical treatment is the most common treatment for breast cancer.[7],[8] First-line drugs of chemical treatment are anthracyclines and tamoxifen, and pharmorubicin, a novel kind of anthracyclines, seems to have promising efficacy.[9],[10]

The therapeutic mechanism of pharmorubicin is that pharmorubicin induces intercalation into DNA sequence and inhibits transcription so as repress gene expression of cancer cells. Although pharmorubicin treatment makes breast cancer become a kind of solid tumor with promising prognosis, increasing studies report defects and shortcomings of novel drug.[11],[12] For example, bleeding events always result from chemical treatment. Moreover, long-term use of pharmorubicin seems to cause cardiac dysfunction despite of its promising efficacy.[13],[14] In addition, it remains unclear how pharmorubicin induces cardiac dysfunction in patients with breast cancer. The previous study indicated increased oxygen free radical level was associated with worsen cardiac function, whereas anthracyclines were reported with such effect.[14] However, no report was about effect of pharmorubicin on oxygen free radical level.

Reported with eliminating effect of oxygen free radical, N-acetylcysteine (NAC) plays a pivotal role in treatments of cancer and cardiovascular diseases and has get approval of the USA Food and Drug Administration.[14],[15] Thus, combination therapy of NAC and pharmorubicin may improve cardiac function of patients with breast cancer.

In summary, we hypothesized that pharmorubicin worsened cardiac function of patients with breast cancer through increasing oxygen free radical. Our study was aimed to explore the influence of pharmorubicin on the left ventricular ejection fraction (LVEF) of patients with breast cancer and its potential mechanism.

 Materials and Methods



Research object and grouping

The inclusion criteria and exclusion criteria are reported previously.[16],[17] Three hundred and ninety-nine patients with breast cancer were enrolled for our trial (age ranging from 30 to 70 years, average: 45. 1 ± 9. 4 years). Group I consisted of 135 samples, who were under treatment of pharmorubicin (200 mg/m2). Group II consisted of 144 samples, who were under treatment of pharmorubicin (360 mg/m2). Group III was used as control group, which consists of 120 samples without treatment of pharmorubicin. This study was under the approval of Local Ethics Committee.

Ultrasonic inspection and measurement

According to routine protocols,[18] color Doppler ultrasonic inspection and measurement were performed to examine the index of cardiac function, including EF and fractional shortening (FS).

Collection of blood Sample

Venous blood was drawn from patients with breast cancer, and separation of hemocytes was performed as reported previously.[19] Hemocytes samples for flow cytometry were prepared.

Flow cytometer detection for oxygen free radical

Oxygen free radical was assessed by flow cytometry with routine protocol.[20] Details were as follows citrate anticoagulation was performed for blood sample. Centrifuge after mixing samples (2100 rpm/min, 5 min). Harvest hemocytes precipitation and resuspend hemocytes in coagulocytes (CGS) buffer solution. Fluorescein isothiocyanate-dichlorofluorescein solution was added and incubated away from light at room temperature. Flow cytometer was performed and examine at absorbance value at exciting wave 488 nm and absorption wave 625 nm.[21]

Data analysis and statistics

SPSS 19.0 software (SPSS, Chicago, IL, USA) was used for data processing. Measurement data are normal distribution to X ± S. T-test was performed for statistical significance. P < 0.05 was considered to be statistically significant.

 Results



Ultrasonic findings of three groups

As showed in [Figure 1], color Doppler ultrasonic examination was performed for three groups, which included 399 samples. Among three groups, patients in Group III had ideal cardiac function, whereas Group I had worst cardiac function. Compared with Group I, Adjunctive therapy of NAC in Group II improved cardiac function, including increased LVEF and FS.{Figure 1}

Analysis of the left ventricular ejection fraction and fractional shortening

Analysis results showed that pharmorubicin treatment indeed jeopardized cardiac function, verified by decreased LVEF and FS. Moreover, NAC abrogated such side effect of pharmorubicin on cardiac function [Figure 2] and [Table 1].{Figure 2}{Table 1}

Detection of oxygen free radical levels in three groups

As described previously, we hypothesized pharmorubicin damaged heart through increasing oxygen free radical level. The results of flow cytometer were showed in [Figure 3] and [Table 2]. Compared with Group III, pharmorubicin treatment significantly increased oxygen free radical level in hemocytes.{Figure 3}{Table 2}

N-acetylcysteine alleviated increased oxygen free radical

We further explored the effect of NAC, and offer additional NAC treatment for patients (showed as II + NAC group). As showed in [Table 3] and [Figure 3], NAC alleviated worsen oxygen free radical induced by pharmorubicin (P < 0. 05), suggesting adjunctive therapy of NAC might abrogate side effect of pharmorubicin through decreasing oxygen free radical.{Table 3}

N-acetylcysteine alleviated cardiac dysfunction induced by pharmorubicin

Further ultrasonic examination proved that NAC indeed alleviated cardiac dysfunction induced by pharmorubicin [Table 4].{Table 4}

 Discussion



Our study proved that pharmorubicin treatment indeed worsen cardiac function in patients with breast cancer, which was consistent with the previous report.[22] In addition, we demonstrated that pharmorubicin cause heart damage through increasing oxygen free radical level while NAC can be an ideal adjunctive drug for pharmorubicin to alleviate its side effect, suggesting that combination therapy of NAC and pharmorubicin should be considered in treatment of breast cancer.

Pharmorubicin was a first-line drug for the treatment of breast cancer with promising tumor-restricted efficacy, but some clinical study indicated pharmorubicin treatment was associated with poor prognosis of cardiovascular diseases, and observed in patients with breast cancer.[23],[24] Despite of unclear mechanisms, recent studies have provided some hints on how pharmorubicin influenced heart. For example, aberrant accumulation of pharmorubicin was found in heart,[25] and in vitro experiment showed that pharmorubicin-induced dysfunction and excessive oxidative stress in both cardiomyocytes and hemocytes.[26] However, there were no reports about how pharmorubicin induced side effects in vivo. Our study found that, in patients with breast cancer, oxygen free radical level of blood was significantly increased after pharmorubicin treatment, and excessive oxidative stress in peripheral blood has been thoroughly proved as a risk factor for cardiomyocytes.[22] Thus, we proved in vivo that pharmorubicin treatment jeopardized cardiac function of patients with breast cancer through increasing oxygen free radical level in hemocytes. Further, we explore potential therapy to alleviated side effect of pharmorubicin. The previous study suggested that NAC was an alternative antioxidant for multiple diseases.[27],[28] Considering its characteristics, we used NAC as an adjunctive drug for patients. We are pleased to find that NAC indeed reduced oxidative stress in patients with breast cancer. Moreover, such treatment improved cardiac function, verified by color Doppler ultrasonic inspection, and measurement. All these findings indicated that side effect of pharmorubicin on cardiac function should be emphasized in clinical treatment, and NAC was recommend as adjunctive drug of pharmorubicin.

Another innovation point of our study is that we demonstrated color Doppler ultrasonic examination could be used as diagnosis tool to assess the cardiac function of patients with breast cancer. In summary, there are three main findings in our study. (1) Pharmorubicin influenced cardiac function of patients with breast cancer, verified by decreased LVEF, and FS. (2) Pharmorubicin increased oxygen free radical level of blood, which resulted in cardiac dysfunction. (3) Application of NAC abrogated side effect of pharmorubicin, and improved cardiac function.

Our study still has some shortcomings, which need further research. (1) Our study is based on a relatively small sample. (2) Direct evidence was warranted for better understanding of how pharmorubicin influenced cardiac function through oxygen free radical level. (3) Knockout mouse models should be established to test our findings.

Pharmorubicin treatment decreased EF and FS of patients with breast cancer through increasing oxygen free radical level in hemocytes. Adjunctive therapy of NAC could be a potential treatment to ameliorated side effect pharmorubicin treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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