<i>Trans</i>-(±)-Kusunokinin Binding to AKR1B1 Inhibits Oxidative Stress and Proteins Involved in Migration in Aggressive Breast Cancer

• Main Authors: Tanotnon Tanawattanasuntorn (Author), Thidarath Rattanaburee (Author), Tienthong Thongpanchang (Author), Potchanapond Graidist (Author)
• Format: Book
• Published: MDPI AG, 2022-11-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antiox11122347; 2076-3921
• Keywords: <i>trans</i>-(±)-kusunokinin; AKR1B1; breast cancer; Therapeutics. Pharmacology; RM1-950
• Source: Antioxidants, Vol 11, Iss 12, p 2347 (2022)

Synthetic <i>trans</i>-(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>±</mo></semantics></math></inline-formula>)-kusunokinin ((<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>±</mo></semantics></math></inline-formula>)KU), a potential anticancer substance, was revealed to have an inhibitory effect on breast cancer. According to the computational modeling prediction, AKR1B1, an oxidative stress and cancer migration protein, could be a target protein of <i>trans</i>-(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>−</mo></semantics></math></inline-formula>)-kusunokinin. In this study, we determined the binding of (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>±</mo></semantics></math></inline-formula>)KU and AKR1B1 on triple-negative breast and non-serous ovarian cancers. We found that (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>±</mo></semantics></math></inline-formula>)KU exhibited a cytotoxic effect that was significantly stronger than zopolrestat (ZP) and epalrestat (EP) (known AKR1B1 inhibitors) on breast and ovarian cancer cells. (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>±</mo></semantics></math></inline-formula>)KU inhibited aldose reductase activity that was stronger than <i>trans</i>-(<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>−</mo></semantics></math></inline-formula>)-arctiin ((<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>−</mo></semantics></math></inline-formula>)AR) but weaker than ZP and EP. Interestingly, (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>±</mo></semantics></math></inline-formula>)KU stabilized AKR1B1 on SKOV3 and Hs578T cells after being heated at 60 and 75 °C, respectively. (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>±</mo></semantics></math></inline-formula>)KU decreased malondialdehyde (MDA), an oxidative stress marker, on Hs578T cells in a dose-dependent manner and the suppression was stronger than EP. Furthermore, (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>±</mo></semantics></math></inline-formula>)KU downregulated AKR1B1 and its downstream proteins, including PKC-δ, NF-κB, AKT, Nrf2, COX2, Twist2 and N-cadherin and up-regulated E-cadherin. (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>±</mo></semantics></math></inline-formula>)KU showed an inhibitory effect on AKR1B1 and its downstream proteins, similar to siRNA-AKR1B1. Interestingly, the combination of siRNA-AKR1B1 with EP or (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>±</mo></semantics></math></inline-formula>)KU showed a greater effect on the suppression of AKR1B1, N-cadherin, E-cadherin and NF-κB than single treatments. Taken together, we concluded that (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mo>±</mo></semantics></math></inline-formula>)KU-bound AKR1B1 leads to the attenuation of cellular oxidative stress, as well as the aggressiveness of breast cancer cell migration.