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. 2020 Jun 26;12(6):1901.
doi: 10.3390/nu12061901.

Dietary Crocin is Protective in Pancreatic Cancer while Reducing Radiation-Induced Hepatic Oxidative Damage

Hamid A Bakshi  1 , Mazhar S Al Zoubi  2 , Faruck L Hakkim  3 , Alaa A A Aljabali  4 , Firas A Rabi  5 , Amin A Hafiz  6 , Khalid M Al-Batanyeh  7 , Bahaa Al-Trad  7 , Prawej Ansari  8 , Mohamed M Nasef  9 , Nitin B Charbe  10 , Saurabh Satija  11   12 , Meenu Mehta  11   12 , Vijay Mishra  11 , Gaurav Gupta  13 , Salem Abobaker  14 , Poonam Negi  15 , Ibrahim M Azzouz  16 , Ashref Ali K Dardouri  17 , Harish Dureja  18 , Parteek Prasher  19 , Dinesh K Chellappan  20 , Kamal Dua  12   15 , Mateus Webba da Silva  1 , Mohamed El Tanani  21 , Paul A McCarron  1 , Murtaza M Tambuwala  1
Affiliations

Dietary Crocin is Protective in Pancreatic Cancer while Reducing Radiation-Induced Hepatic Oxidative Damage

Hamid A Bakshi et al. Nutrients. .

Abstract

Pancreatic cancer is one of the fatal causes of global cancer-related deaths. Although surgery and chemotherapy are standard treatment options, post-treatment outcomes often end in a poor prognosis. In the present study, we investigated anti-pancreatic cancer and amelioration of radiation-induced oxidative damage by crocin. Crocin is a carotenoid isolated from the dietary herb saffron, a prospect for novel leads as an anti-cancer agent. Crocin significantly reduced cell viability of BXPC3 and Capan-2 by triggering caspase signaling via the downregulation of Bcl-2. It modulated the expression of cell cycle signaling proteins P53, P21, P27, CDK2, c-MYC, Cyt-c and P38. Concomitantly, crocin treatment-induced apoptosis by inducing the release of cytochrome c from mitochondria to cytosol. Microarray analysis of the expression signature of genes induced by crocin showed a substantial number of genes involved in cell signaling pathways and checkpoints (723) are significantly affected by crocin. In mice bearing pancreatic tumors, crocin significantly reduced tumor burden without a change in body weight. Additionally, it showed significant protection against radiation-induced hepatic oxidative damage, reduced the levels of hepatic toxicity and preserved liver morphology. These findings indicate that crocin has a potential role in the treatment, prevention and management of pancreatic cancer.

Keywords: apoptosis; cell cycle; crocin; hepatic injury; pancreatic cancer; radiation.

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Conflict of interest statement

Authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
In vitro inhibition of thiobarbituric acid reacting substances (TBRS) by crocin. Data presented as mean ± SD of triplicates of three independent experiments. .*Asterisks represents significance (* p < 0.05; ** p < 0.01)
Figure 2
Figure 2
Role of crocin on BXPC3 and Capan-2 cells caspase signaling. BXPC3 and Capan-2 cells treated with different concentration (10, 20 and 40 µg/mL) of crocin for 24 h The whole-cell lysate prepared from crocin treated BXPC3 and Capan-2 cells and resolved in SDS PAGE. Analysis. Resolved proteins immune probed with BAX, Bcl2, Caspase3 and Caspase 9 antibodies. β-actin as a loading control. (A) Dose-dependent effect of Crocin on BXPC3 caspase signaling and protein band quantification by densitometric analysis; (B) dose-dependent effect of crocin on Capan-2 caspase signaling and protein band quantification by densitometric analysis with control being 100%.
Figure 3
Figure 3
Crocin induced release of mitochondrial cytochrome c in BXPC3 cells. Release of cytochrome c from mitochondria to the cytosol was detected in BxPC-3 cells treated with crocin (10 µg/mL) at a time point of 0, 12, 24 and 36 h. The protein bands were subsequently quantified by densitometric analysis with that of control being 100% as shown just below the immunoblot data. Data represented the mean ± SEM of three independent experiments.
Figure 4
Figure 4
Effect of crocin on cell cycle signaling proteins in BXPC3 and Capan-2 cells. BXPC3 and Capan-2 cells treated with different concentration (10, 20 and 40 µg/mL) of crocin for 24 h The whole-cell lysate prepared from crocin treated BXPC3 and Capan-2 cells and resolved in SDS-PAGE. Resolved proteins immune probed with P53, P21Cip1, P27Kip1, CDK2, c-Myc, Cyto-C and P38 antibodies. β-actin as loading control; (A) Dose-dependent effect of Crocin on BXPC3 cell cycle signaling and protein band quantification by densitometric analysis; (B) dose-dependent effect of crocin on Capan-2 cell cycle signaling and protein band quantification by densitometric analysis with control being 100%. Data represent mean ± SEM. * indicates significant differences compared to control (* p0.05; ** p0.01).
Figure 5
Figure 5
Crocin induced gene signatures of BXPC3 cells. BxPC3 cells (1 × 107) were treated with crocin (10 µg/mL). Total RNA was isolated from crocin treated BXPC3 cells and hybridized with Agilent’s Human Array G8451B.
Figure 6
Figure 6
Efficacy of crocin on in vivo pancreatic tumor remission and bodyweight of tumor-bearing mice. (A) Tumor remission by 50 mg/kg and 100 mg/kg of crocin treatment; (B) body weight of tumor-bearing mice; (C) tumor remission; (a) control; (b) 50 mg/kg treatment of crocin; (c) 100 mg/kg treatment of crocin.
Figure 7
Figure 7
Restoration of radiation-induced liver damage by crocin. Photomicrographs of liver tissue. (A) Control groups: Normal histological appearance of liver tissue; (B) DDW + 4Gy-treated groups: hyperplasia (arrow), hemorrhage, atrophy and red hyaline (arrowhead); (C) crocin (100 mg/kg, but) + 4Gy-treated groups: regular hepatocytes in the most region and mild activated Kupffer cells. H&E Staining, original magnifications: ×200.
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