Combination Therapy of Lactobacillus plantarum Supernatant and 5-Fluouracil Increases Chemosensitivity in Colorectal Cancer Cells

J Microbiol Biotechnol. 2016 Aug 28;26(8):1490-503. doi: 10.4014/jmb.1605.05024.

Abstract

Colorectal cancer (CRC) is the third most common cancer in the world. Although 5-fluorouracil (5-FU) is the representative chemotherapy drug for colorectal cancer, it has therapeutic limits due to its chemoresistant characteristics. Colorectal cancer cells can develop into cancer stem cells (CSCs) with self-renewal potential, thereby causing malignant tumors. The human gastrointestinal tract contains a complex gut microbiota that is essential for the host's homeostasis. Recently, many studies have reported correlations between gut flora and the onset, progression, and treatment of CRC. The present study confirms that the most representative symbiotic bacteria in humans, Lactobacillus plantarum (LP) supernatant (SN), selectively inhibit the characteristics of 5-FU-resistant colorectal cancer cells (HT-29 and HCT- 116). LP SN inhibited the expression of the specific markers CD44, 133, 166, and ALDH1 of CSCs. The combination therapy of LP SN and 5-FU inhibited the survival of CRCs and led to cell death by inducing caspase-3 activity. The combination therapy of LP SN and 5-FU induced an anticancer mechanism by inactivating the Wnt/β-catenin signaling of chemoresistant CRC cells, and reducing the formation and size of colonospheres. In conclusion, our results show that LP SN can enhance the therapeutic effect of 5-FU for colon cancer, and reduce colorectal cancer stem-like cells by reversing the development of resistance to anticancer drugs. This implies that probiotic substances may be useful therapeutic alternatives as biotherapeutics for chemoresistant CRC.

Keywords: 5-Fluorouracil; Lactobacillus plantarum; cancer stem cells; chemoresistant; colorectal cancer cells.

MeSH terms

  • AC133 Antigen / genetics
  • Aldehyde Dehydrogenase 1 Family
  • Antigens, CD / genetics
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Axin Protein / metabolism
  • Caspase 3 / genetics
  • Cell Adhesion Molecules, Neuronal / genetics
  • Colorectal Neoplasms
  • Culture Media / chemistry
  • Drug Resistance, Neoplasm
  • Drug Synergism*
  • Fetal Proteins / genetics
  • Fluorouracil / pharmacology*
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Hyaluronan Receptors / genetics
  • Isoenzymes / genetics
  • Lactobacillus plantarum / chemistry*
  • Lactobacillus plantarum / growth & development
  • Neoplastic Stem Cells / drug effects*
  • Polymerase Chain Reaction
  • Probiotics / pharmacology*
  • Retinal Dehydrogenase / genetics
  • Tankyrases / metabolism
  • Wnt Signaling Pathway / drug effects
  • beta Catenin / metabolism

Substances

  • AC133 Antigen
  • ALCAM protein, human
  • AXIN1 protein, human
  • Antigens, CD
  • Antineoplastic Agents
  • Axin Protein
  • Cell Adhesion Molecules, Neuronal
  • Culture Media
  • Fetal Proteins
  • Hyaluronan Receptors
  • Isoenzymes
  • PROM1 protein, human
  • beta Catenin
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A1 protein, human
  • Retinal Dehydrogenase
  • Tankyrases
  • TNKS protein, human
  • Caspase 3
  • Fluorouracil