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. 2017 Apr 4:8:132.
doi: 10.3389/fphar.2017.00132. eCollection 2017.

Curcumin Ameliorates Cisplatin-Induced Nephrotoxicity and Potentiates Its Anticancer Activity in SD Rats: Potential Role of Curcumin in Breast Cancer Chemotherapy

Parveen Kumar  1 , Chandana C Barua  2 , Kunjbihari Sulakhiya  1 , Rajeev Kumar Sharma  3
Affiliations

Curcumin Ameliorates Cisplatin-Induced Nephrotoxicity and Potentiates Its Anticancer Activity in SD Rats: Potential Role of Curcumin in Breast Cancer Chemotherapy

Parveen Kumar et al. Front Pharmacol. .

Abstract

Breast malignant neoplastic disease is one of the most complex diseases, as it is a multifactorial disease in which virtually all the targets are instantly or indirectly inter-reliant on each other. Cisplatin (CIS), an inorganic antineoplastic agent is widely utilized in the treatment of various solid tumors including breast cancer. Despite everything, its clinical use is limited, due to ototoxicity, peripheral neuropathy, and nephrotoxicity. The present work was directed to assess the combined result of curcumin (CUR) and CIS in 7, 12-dimethyl benz[a]anthracene (DMBA) induced breast cancer in rats and the prevention of nephrotoxicity induced by the latter. CIS-induced nephrotoxicity was assessed by change in body weight, kidney weight, altered levels of BUN, creatinine, TNF-α, IL-6, IL-8, IL-10, and histopathology of the kidney. Anticancer activity was assessed by measurement of tumor weight, tumor volume, % tumor inhibition, levels of PPAR-γ, and BDNF in mammary tumors and histopathology of mammary tumors. CUR pre-treatment mitigated nephrotoxicity by reducing the inflammatory markers (TNF-α, IL-6, and IL-8; p < 0.001). Further, it reduced mammary cancer via increasing the expression of PPAR-γ (p < 0.001) and decreasing the expression of BDNF (p < 0.001) in mammary tumors. It also reduced tumor volume, further postulating that CUR might adjunct the anticancer activity of the CIS. To the best of our knowledge, this is the first report, which showed that CUR ameliorated CIS-induced nephrotoxicity and improved its anticancer activity in DMBA induced breast cancer in female Sprague-Dawley rats.

Keywords: brain-derived neurotrophic factor; breast cancer; cisplatin; curcumin; nephrotoxicity; peroxisome proliferator activated receptor-γ.

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Figures

Figure 1
Figure 1
Timeline of the study.
Figure 2
Figure 2
Combined effect of curcumin and cisplatin on tumor weight in breast cancer rats. All the values were expressed as mean ± SEM (n = 8). *P < 0.05, ***P < 0.001. a vs. breast cancer control, b vs. cisplatin, and c vs. curcumin. Where BCC is breast cancer control, CUR is curcumin, CIS is cisplatin, and CUR + CIS is pre-treatment of curcumin (120 mg/kg) for 5 days, followed by single dose of cisplatin (7.5 mg/kg) on the 5th day.
Figure 3
Figure 3
Effect of curcumin plus cisplatin treatment on inflammatory markers in breast cancer (A–D). All the values were expressed as mean ± SEM (n = 8). *P < 0.05, **P < 0.01, ***P < 0.001. a vs. breast cancer control, b vs. cisplatin. Where BCC is breast cancer control, CUR is curcumin, CIS is cisplatin, and CUR + CIS is pre-treatment of curcumin (120 mg/kg) for 5 days, followed by single dose of cisplatin (7.5 mg/kg) on the 5th day.
Figure 4
Figure 4
Combined anticancer effect of curcumin pre-treatment and cisplatin on tumor volume (mm3) in breast cancer rats. All the values were expressed as mean ± SEM (n = 8). *P < 0.05, **P < 0.01. a vs. breast cancer control. Where BCC is breast cancer control, CUR is curcumin, CIS is cisplatin, and CUR + CIS is pre-treatment of curcumin (120 mg/kg) for 5 days, followed by single dose of cisplatin (7.5 mg/kg) on the 5th day.
Figure 5
Figure 5
Effect of curcumin plus cisplatin treatment on BDNF in breast cancer rats. All the values were expressed as mean ± SEM (n = 8). **P < 0.01, ***P < 0.001. a vs. breast cancer control, b vs. cisplatin, and c vs. curcumin. Where BCC is breast cancer control, CUR is curcumin, CIS is cisplatin, and CUR + CIS is pre-treatment of curcumin (120 mg/kg) for 5 days, followed by single dose of cisplatin (7.5 mg/kg) on the 5th day.
Figure 6
Figure 6
Western blots of PPAR-γ and BDNF in mammary tumors. Western blots of PPAR-γ and BDNF levels in mammary tumors after combined treatment of curcumin and cisplatin in breast cancer rats. Where lane a is breast cancer control, b is curcumin, c is cisplatin, and d is Curcumin + Cisplatin. Results were normalized with respect to actin. Similar results were obtained in three independent set of experiments. All values were expressed as mean ± SEM (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001; a vs. breast cancer control & b vs. cisplatin.
Figure 7
Figure 7
Histopathological changes in the kidney after combined treatment of curcumin and cisplatin in breast cancer rats. Transverse section of cancer control rat kidney (A), kidney after treatment with curcumin (B), cisplatin-treated (C), and pre-treatment with curcumin (D). Sections were stained with Mayer's hematoxylin counterstained with eosin and observed under magnification of 40X. Quantitative analysis of kidney histopathology (E) where; control rat kidney (A), curcumin treated kidney (B), cisplatin-treated kidney (C), and curcumin treated kidney (D). ++++, Very severe; +++, Severe; ++, Moderate; +, Mild; –, None.
Figure 8
Figure 8
Histopathological changes were seen in mammary tumors after combined treatment of curcumin and cisplatin. (A) Breast cancer control group, (B) mammary tumor after treatment with curcumin: pronounced cell pleomorphism and a low grade of differentiation are demonstrated by multinucleated giant cells, (C) cisplatin treated mammary tumor with decreased cell density and higher level of fibrosis as sign of a therapeutic effect, (D) curcumin pre-treated mammary tumor after 5 days. The glandular structure as an indicator for a functional differentiation noticeable. (E) Quantitative analysis of histopathological studies in mammary tumor where, breast cancer control (A), curcumin treated mammary tumor (B), cisplatin-treated mammary tumor (C), and curcumin pretreated mammary tumor (D).
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