Effects of withania somnifera and tinospora cordifolia extracts on the side population phenotype of human epithelial cancer cells

Toward targeting multidrug resistance in cancer

Naseer Maliyakkal, Asmy Appadath Beeran, Sai A. Balaji, Nayanabhirama Udupa, Sreedhara Ranganath Pai, Annapoorni Rangarajan

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Recent reports suggest the existence of a subpopulation of stem-like cancer cells, termed as cancer stem cells (CSCs), which bear functional and phenotypic resemblance with the adult, tissue-resident stem cells. Side population (SP) assay based on differential efflux of Hoechst 33342 has been effectively used for the isolation of CSCs. The drug resistance properties of SP cells are typically due to the increased expression of ABC transporters leading to drug efflux. Conventionally used chemotherapeutic drugs may often leads to an enrichment of SP, revealing their inability to target the drug-resistant SP and CSCs. Thus, identification of agents that can reduce the SP phenotype is currently in vogue in cancer therapeutics. Withania somnifera (WS) and Tinospora cordifolia (TC) have been used in Ayurveda for treating various diseases, including cancer. In the current study, we have investigated the effects of ethanolic (ET) extracts of WS and TC on the cancer SP phenotype. Interestingly, we found significant decrease in SP on treatment with TC-ET, but not with WS-ET. The SP-inhibitory TC-ET was further fractionated into petroleum ether (TC-PET), dichloromethane (TC-DCM), and n-butyl alcohol (TC-nBT) fractions using bioactivity-guided fractionation. Our data revealed that TC-PET and TC-DCM, but not TC-nBT, significantly inhibited SP in a dose-dependent manner. Furthermore, flow cytometry-based functional assays revealed that TC-PET and TC-DCM significantly inhibited ABC-B1 and ABC-G2 transporters and sensitized cancer cells toward chemotherapeutic drug-mediated cytotoxicity. Thus, the TC-PET and TC-DCM may harbor phytochemicals with the potential to reverse the drug-resistant phenotype, thus improving the efficacy of cancer chemotherapy.

Original languageEnglish
Pages (from-to)156-171
Number of pages16
JournalIntegrative Cancer Therapies
Volume14
Issue number2
DOIs
Publication statusPublished - 17-03-2015

Fingerprint

Tinospora
Withania
Multiple Drug Resistance
Epithelial Cells
Phenotype
Population
Neoplasms
Neoplastic Stem Cells
ATP-Binding Cassette Transporters
Pharmaceutical Preparations
Side-Population Cells
1-Butanol
Methylene Chloride
Phytochemicals
Drug Resistance

All Science Journal Classification (ASJC) codes

  • Oncology
  • Complementary and alternative medicine

Cite this

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title = "Effects of withania somnifera and tinospora cordifolia extracts on the side population phenotype of human epithelial cancer cells: Toward targeting multidrug resistance in cancer",
abstract = "Recent reports suggest the existence of a subpopulation of stem-like cancer cells, termed as cancer stem cells (CSCs), which bear functional and phenotypic resemblance with the adult, tissue-resident stem cells. Side population (SP) assay based on differential efflux of Hoechst 33342 has been effectively used for the isolation of CSCs. The drug resistance properties of SP cells are typically due to the increased expression of ABC transporters leading to drug efflux. Conventionally used chemotherapeutic drugs may often leads to an enrichment of SP, revealing their inability to target the drug-resistant SP and CSCs. Thus, identification of agents that can reduce the SP phenotype is currently in vogue in cancer therapeutics. Withania somnifera (WS) and Tinospora cordifolia (TC) have been used in Ayurveda for treating various diseases, including cancer. In the current study, we have investigated the effects of ethanolic (ET) extracts of WS and TC on the cancer SP phenotype. Interestingly, we found significant decrease in SP on treatment with TC-ET, but not with WS-ET. The SP-inhibitory TC-ET was further fractionated into petroleum ether (TC-PET), dichloromethane (TC-DCM), and n-butyl alcohol (TC-nBT) fractions using bioactivity-guided fractionation. Our data revealed that TC-PET and TC-DCM, but not TC-nBT, significantly inhibited SP in a dose-dependent manner. Furthermore, flow cytometry-based functional assays revealed that TC-PET and TC-DCM significantly inhibited ABC-B1 and ABC-G2 transporters and sensitized cancer cells toward chemotherapeutic drug-mediated cytotoxicity. Thus, the TC-PET and TC-DCM may harbor phytochemicals with the potential to reverse the drug-resistant phenotype, thus improving the efficacy of cancer chemotherapy.",
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Effects of withania somnifera and tinospora cordifolia extracts on the side population phenotype of human epithelial cancer cells : Toward targeting multidrug resistance in cancer. / Maliyakkal, Naseer; Appadath Beeran, Asmy; Balaji, Sai A.; Udupa, Nayanabhirama; Ranganath Pai, Sreedhara; Rangarajan, Annapoorni.

In: Integrative Cancer Therapies, Vol. 14, No. 2, 17.03.2015, p. 156-171.

Research output: Contribution to journalArticle

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AU - Maliyakkal, Naseer

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AU - Ranganath Pai, Sreedhara

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