Bicarbonate transport inhibitor SITS modulates pH homeostasis triggering apoptosis of Dalton's lymphoma: implication of novel molecular mechanisms

Mol Cell Biochem. 2014 Dec;397(1-2):167-78. doi: 10.1007/s11010-014-2184-2. Epub 2014 Aug 15.


Bicarbonate transporter (BCT) plays a crucial role in maintaining pH homeostasis of tumor cells by import of HCO3(-). This helps the tumor cells in manifesting extracellular tumor acidosis, accompanied by a relative intracellular alkalinization, which in turn promotes tumor progression. Therefore, blocking BCT-mediated HCO3(-) transport is envisaged as a promising anticancer therapeutic approach. Thus, using a murine model of a T cell lymphoma, designated as Dalton's lymphoma (DL), in the present in vitro investigation the antitumor consequences of blocking BCT function by its inhibitor 4-acetamido-4-isothiocyanostilbene-2,2-disulfonate (SITS) were explored. Treatment of DL cells with SITS resulted in an increase in the extracellular pH, associated with a decline in DL cell survival and augmented induction of apoptosis. BCT inhibition also elevated the expression of cytochrome c, caspase-9, caspase-3, Bax, reactive oxygen species, and nitric oxide along with inhibition of HSP-70 and Bcl2, which regulate tumor cell survival and apoptosis. SITS-treated DL cells displayed upregulated production of IFN-γ and IL-6 along with a decline of IL-10. Treatment of DL cells with SITS also inhibited the expression of fatty acid synthase, which is crucial for membrane biogenesis in neoplastic cells. The expression of lactate transporter MCT-1 and multidrug resistance regulating protein MRP-1 got inhibited along with hampered uptake of glucose and lactate production in SITS-treated DL cells. Thus, the declined tumor cell survival following inhibition of BCT could be the consequence of interplay of several inter-connected regulatory molecular events. The outcome of this study indicates the potential of BCT inhibition as a novel therapeutic approach for treatment of hematological malignancies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / pharmacology*
  • Animals
  • Anion Transport Proteins / antagonists & inhibitors*
  • Anion Transport Proteins / genetics
  • Anion Transport Proteins / metabolism
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Bicarbonates / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Homeostasis / drug effects*
  • Homeostasis / genetics
  • Hydrogen-Ion Concentration
  • Lymphoma, T-Cell / drug therapy*
  • Lymphoma, T-Cell / genetics
  • Lymphoma, T-Cell / metabolism
  • Lymphoma, T-Cell / pathology
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Symporters / antagonists & inhibitors*
  • Symporters / genetics
  • Symporters / metabolism


  • Anion Transport Proteins
  • Apoptosis Regulatory Proteins
  • Bicarbonates
  • Cytokines
  • Neoplasm Proteins
  • Slc4a11 protein, mouse
  • Symporters
  • 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid