Abstract
Hypoxia-regulated protein carbonic anhydrase IX (CA IX) is up-regulated in different tumor entities and correlated with poor prognosis in breast cancer patients. Due to the radio- and chemotherapy resistance of solid hypoxic tumors, derivatives of betulinic acid (BA), a natural compound with anticancer properties, seem to be promising to benefit these cancer patients. We synthesized new betulin sulfonamides and determined their cytotoxicity in different breast cancer cell lines. Additionally, we investigated their effects on clonogenic survival, cell death, extracellular pH, HIF-1α, CA IX and CA XII protein levels and radiosensitivity. Our study revealed that cytotoxicity increased after treatment with the betulin sulfonamides compared to BA or their precursors, especially in triple-negative breast cancer (TNBC) cells. CA IX activity as well as CA IX and CA XII protein levels were reduced by the betulin sulfonamides. We observed elevated inhibitory efficiency against protumorigenic processes such as proliferation and clonogenic survival and the promotion of cell death and radiosensitivity compared to the precursor derivatives. In particular, TNBC cells showed benefit from the addition of sulfonamides onto BA and revealed that betulin sulfonamides are promising compounds to treat more aggressive breast cancers, or are at the same level against less aggressive breast cancer cells.
Highlights
Breast cancer is the most common cancer in women in developed countries [1]
Breast cancer cells can be characterized by evaluation of the receptor status of ER, PR and HER2 [30]
Proof of the receptors in the breast cancer cell lines was detected by Western blot: SKBR3 as a HER2-positive cell line, T47D as an ER- and PR-positive cell line and MCF-7 as an ER-positive cell line (Figure 2A, Table 1)
Summary
Breast cancer is the most common cancer in women in developed countries [1]. Therapies include surgery, systemic chemotherapy, radiotherapy, and hormone therapy, with new drugs continuously being developed [2]. Cancer-specific deaths of women are, in most cases, due to breast cancer. Hormone receptor- (estrogen (ER) and progesterone (PR)) and HER2-negative tumors are resistant to therapy and linked to poor prognosis [2]. Hypoxic areas in tumors caused by poor oxygen supply are known for their resistance to therapy. Both characteristics impose new possible focal points in the development of breast cancer therapeutics [3]
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