Combination of cisplatin and bromelain exerts synergistic cytotoxic effects against breast cancer cell line MDA-MB-231 in vitro

Ahmad Zaim Mat Pauzi, Swee Keong Yeap, Nadiah Abu, Kian Lam Lim, Abdul Rahman Omar, Suraini Abdul Aziz, Adam Leow Thean Chow, Tamilselvan Subramani, Soon Guan Tan, Noorjahan Banu Alitheen

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Abstract

Background: Bromelain, which is a cysteine endopeptidase commonly found in pineapple stems, has been investigated as a potential anti-cancer agent for the treatment of breast cancer. However, information pertaining to the effects of combining bromelain with existing chemotherapeutic drugs remains scarce. This study aimed to investigate the possible synergistic cytotoxic effects of using bromelain in combination with cisplatin on MDA-MB-231 human breast cancer cells. Method: MDA-MB-231 cells were treated with different concentrations (0.24-9.5μM) of bromelain or cisplatin alone, as well as four different combinations of these two agents to assess their individual and combination effects after 24 and 48h. Cell viability was analyzed using an MTT assay. The induction of apoptosis was assessed using cell cycle analysis and an Annexin V-FITC assay. The role of the mitochondrial membrane potential in the apoptotic process was assessed using a JC-1 staining assay. Apoptotic protein levels were assessed by western blot analysis and proteome profiling using an antibody array kit. Results: Single-agent treatment with cisplatin or bromelain led to dose- and time-dependent decreases in the viability of the MDA-MB-231 cells at 24 and 48h. Furthermore, most of the combinations evaluated in this study displayed synergistic effects against MDA-MB-231 cells at 48h, with combination 1 (bromelain 2μM+cisplatin 1.5μM) exhibiting the greatest synergistic effect (P=0.000). The results of subsequent assays indicated that combination 1 treatment induced apoptosis via mitochondria-mediated pathway. Combination 1 also resulted in significant decreases in the levels of several apoptotic proteins such as Bcl-x and HSP70, compared with bromelain (P=0.002 and 0.000, respectively) or cisplatin (P=0.000 and 0.001, respectively) single treatment. Notably, MDA-MB-231 cells treated with combination 1 showed increased levels of the pro-apoptotic proteins Bax compared with those treated with bromelain (P=0.000) or cisplatin single treatment (P=0.043). Conclusion: Bromelain in combination with cisplatin synergistically enhanced the induction of apoptosis in MDA-MB-231 cells.

Original languageEnglish
Article number46
JournalChinese Medicine (United Kingdom)
Volume11
Issue number1
DOIs
Publication statusPublished - 15 Nov 2016
Externally publishedYes

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Bromelains
Cisplatin
Breast Neoplasms
Cell Line
Apoptosis
Cysteine Endopeptidases
Ananas
In Vitro Techniques
Apoptosis Regulatory Proteins
Fluorescein-5-isothiocyanate
Mitochondrial Membrane Potential
Annexin A5
Proteome
Cell Survival
Cell Cycle
Mitochondria
Proteins
Western Blotting
Staining and Labeling

ASJC Scopus subject areas

  • Pharmacology
  • Complementary and alternative medicine

Cite this

Combination of cisplatin and bromelain exerts synergistic cytotoxic effects against breast cancer cell line MDA-MB-231 in vitro. / Pauzi, Ahmad Zaim Mat; Yeap, Swee Keong; Abu, Nadiah; Lim, Kian Lam; Omar, Abdul Rahman; Aziz, Suraini Abdul; Chow, Adam Leow Thean; Subramani, Tamilselvan; Tan, Soon Guan; Alitheen, Noorjahan Banu.

In: Chinese Medicine (United Kingdom), Vol. 11, No. 1, 46, 15.11.2016.

Research output: Contribution to journalArticle

Pauzi, Ahmad Zaim Mat ; Yeap, Swee Keong ; Abu, Nadiah ; Lim, Kian Lam ; Omar, Abdul Rahman ; Aziz, Suraini Abdul ; Chow, Adam Leow Thean ; Subramani, Tamilselvan ; Tan, Soon Guan ; Alitheen, Noorjahan Banu. / Combination of cisplatin and bromelain exerts synergistic cytotoxic effects against breast cancer cell line MDA-MB-231 in vitro. In: Chinese Medicine (United Kingdom). 2016 ; Vol. 11, No. 1.
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abstract = "Background: Bromelain, which is a cysteine endopeptidase commonly found in pineapple stems, has been investigated as a potential anti-cancer agent for the treatment of breast cancer. However, information pertaining to the effects of combining bromelain with existing chemotherapeutic drugs remains scarce. This study aimed to investigate the possible synergistic cytotoxic effects of using bromelain in combination with cisplatin on MDA-MB-231 human breast cancer cells. Method: MDA-MB-231 cells were treated with different concentrations (0.24-9.5μM) of bromelain or cisplatin alone, as well as four different combinations of these two agents to assess their individual and combination effects after 24 and 48h. Cell viability was analyzed using an MTT assay. The induction of apoptosis was assessed using cell cycle analysis and an Annexin V-FITC assay. The role of the mitochondrial membrane potential in the apoptotic process was assessed using a JC-1 staining assay. Apoptotic protein levels were assessed by western blot analysis and proteome profiling using an antibody array kit. Results: Single-agent treatment with cisplatin or bromelain led to dose- and time-dependent decreases in the viability of the MDA-MB-231 cells at 24 and 48h. Furthermore, most of the combinations evaluated in this study displayed synergistic effects against MDA-MB-231 cells at 48h, with combination 1 (bromelain 2μM+cisplatin 1.5μM) exhibiting the greatest synergistic effect (P=0.000). The results of subsequent assays indicated that combination 1 treatment induced apoptosis via mitochondria-mediated pathway. Combination 1 also resulted in significant decreases in the levels of several apoptotic proteins such as Bcl-x and HSP70, compared with bromelain (P=0.002 and 0.000, respectively) or cisplatin (P=0.000 and 0.001, respectively) single treatment. Notably, MDA-MB-231 cells treated with combination 1 showed increased levels of the pro-apoptotic proteins Bax compared with those treated with bromelain (P=0.000) or cisplatin single treatment (P=0.043). Conclusion: Bromelain in combination with cisplatin synergistically enhanced the induction of apoptosis in MDA-MB-231 cells.",
author = "Pauzi, {Ahmad Zaim Mat} and Yeap, {Swee Keong} and Nadiah Abu and Lim, {Kian Lam} and Omar, {Abdul Rahman} and Aziz, {Suraini Abdul} and Chow, {Adam Leow Thean} and Tamilselvan Subramani and Tan, {Soon Guan} and Alitheen, {Noorjahan Banu}",
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AU - Pauzi, Ahmad Zaim Mat

AU - Yeap, Swee Keong

AU - Abu, Nadiah

AU - Lim, Kian Lam

AU - Omar, Abdul Rahman

AU - Aziz, Suraini Abdul

AU - Chow, Adam Leow Thean

AU - Subramani, Tamilselvan

AU - Tan, Soon Guan

AU - Alitheen, Noorjahan Banu

PY - 2016/11/15

Y1 - 2016/11/15

N2 - Background: Bromelain, which is a cysteine endopeptidase commonly found in pineapple stems, has been investigated as a potential anti-cancer agent for the treatment of breast cancer. However, information pertaining to the effects of combining bromelain with existing chemotherapeutic drugs remains scarce. This study aimed to investigate the possible synergistic cytotoxic effects of using bromelain in combination with cisplatin on MDA-MB-231 human breast cancer cells. Method: MDA-MB-231 cells were treated with different concentrations (0.24-9.5μM) of bromelain or cisplatin alone, as well as four different combinations of these two agents to assess their individual and combination effects after 24 and 48h. Cell viability was analyzed using an MTT assay. The induction of apoptosis was assessed using cell cycle analysis and an Annexin V-FITC assay. The role of the mitochondrial membrane potential in the apoptotic process was assessed using a JC-1 staining assay. Apoptotic protein levels were assessed by western blot analysis and proteome profiling using an antibody array kit. Results: Single-agent treatment with cisplatin or bromelain led to dose- and time-dependent decreases in the viability of the MDA-MB-231 cells at 24 and 48h. Furthermore, most of the combinations evaluated in this study displayed synergistic effects against MDA-MB-231 cells at 48h, with combination 1 (bromelain 2μM+cisplatin 1.5μM) exhibiting the greatest synergistic effect (P=0.000). The results of subsequent assays indicated that combination 1 treatment induced apoptosis via mitochondria-mediated pathway. Combination 1 also resulted in significant decreases in the levels of several apoptotic proteins such as Bcl-x and HSP70, compared with bromelain (P=0.002 and 0.000, respectively) or cisplatin (P=0.000 and 0.001, respectively) single treatment. Notably, MDA-MB-231 cells treated with combination 1 showed increased levels of the pro-apoptotic proteins Bax compared with those treated with bromelain (P=0.000) or cisplatin single treatment (P=0.043). Conclusion: Bromelain in combination with cisplatin synergistically enhanced the induction of apoptosis in MDA-MB-231 cells.

AB - Background: Bromelain, which is a cysteine endopeptidase commonly found in pineapple stems, has been investigated as a potential anti-cancer agent for the treatment of breast cancer. However, information pertaining to the effects of combining bromelain with existing chemotherapeutic drugs remains scarce. This study aimed to investigate the possible synergistic cytotoxic effects of using bromelain in combination with cisplatin on MDA-MB-231 human breast cancer cells. Method: MDA-MB-231 cells were treated with different concentrations (0.24-9.5μM) of bromelain or cisplatin alone, as well as four different combinations of these two agents to assess their individual and combination effects after 24 and 48h. Cell viability was analyzed using an MTT assay. The induction of apoptosis was assessed using cell cycle analysis and an Annexin V-FITC assay. The role of the mitochondrial membrane potential in the apoptotic process was assessed using a JC-1 staining assay. Apoptotic protein levels were assessed by western blot analysis and proteome profiling using an antibody array kit. Results: Single-agent treatment with cisplatin or bromelain led to dose- and time-dependent decreases in the viability of the MDA-MB-231 cells at 24 and 48h. Furthermore, most of the combinations evaluated in this study displayed synergistic effects against MDA-MB-231 cells at 48h, with combination 1 (bromelain 2μM+cisplatin 1.5μM) exhibiting the greatest synergistic effect (P=0.000). The results of subsequent assays indicated that combination 1 treatment induced apoptosis via mitochondria-mediated pathway. Combination 1 also resulted in significant decreases in the levels of several apoptotic proteins such as Bcl-x and HSP70, compared with bromelain (P=0.002 and 0.000, respectively) or cisplatin (P=0.000 and 0.001, respectively) single treatment. Notably, MDA-MB-231 cells treated with combination 1 showed increased levels of the pro-apoptotic proteins Bax compared with those treated with bromelain (P=0.000) or cisplatin single treatment (P=0.043). Conclusion: Bromelain in combination with cisplatin synergistically enhanced the induction of apoptosis in MDA-MB-231 cells.

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