The common diabetes drug metformin can diminish the action of citral against Rhabdomyosarcoma cells in vitro

Abstract

Rhabdomyosarcoma (RMS) is a rare type of soft tissue sarcoma most commonly found in pediatric patients. Despite progress, new and improved drug regimens are needed to increase survival rates. Citral, a natural product plant oil can induce cell death in cancer cells. Another compound, metformin, isolated originally from French lilac and used by diabetics, has been shown to reduce the incidence of cancer in these patients. Application of citral to RMS cells showed increase in cell death, and RD and RH30 cells showed half maximal inhibitory concentration (IC50) values as low as 36.28 μM and 62.37 μM, respectively. It was also shown that the citral initiated cell apoptosis through an increase in reactive oxygen species (ROS) and free calcium. In comparison, metformin only showed moderate cell death in RMS cell lines at a very high concentration (1,000 μM). Combinatorial experiments, however, indicated that citral and metformin worked antagonistically when used together. In particular, the ability of metformin to quench the ROS induced by citral could lead to the suppression of activity. These results clearly indicate that while clinical use of citral is a promising anti‐tumor therapy, caution should be exercised in patients using metformin for diabetes.

Citral inhibits the nociception in the rat formalin test: effect of metformin and blockers of opioid receptor and the NO-cGMP-K+ channel pathway

“…However, metformin was able to decrease the citral-induced antinociceptive action during the phase two of the formalin test (Figure 4). This last result comes to an agreement with the ability of metformin to block the action of citral against rhabdomyosarcoma cells in vitro (Duan et al 2021).…”

Adverse Effects of Metformin From Diabetes to COVID-19, Cancer, Neurodegenerative Diseases, and Aging: Is VDAC1 a Common Target?

“… Zhang et al (2017) revealed that treatment with metformin increased VDAC expression and decreased superoxide dismutase 1 (SOD1) in PCOS-like rats compared to control rats ( Zhang et al, 2017 ). In addition, metformin in the presence of citral, but not in its absence, increased VDAC expression ( Duan et al, 2021 ). Moreover, VDAC1 is overexpressed in diseases that were found to be modulated by metformin ( Table 1 ).…”

“…Moreover, in the cortical region, plasmalemmal VDAC1 (pl-VDAC1) was found as oligomers in areas where metformin induced Aβ-aggregate accumulation, and apoptotic neurons were observed ( Wijesekara et al, 2017 ). In addition, metformin increased VDAC1 expression levels in NCaP cells ( Loubiere et al, 2017 ) and in polycystic ovary syndrome-like rats ( Zhang et al, 2017 ), and in the presence of citral ( Duan et al, 2021 ).…”

“…In addition, overexpression of VDAC1 is induced by various apoptosis-inducing conditions such as chemotherapy drugs, UV irradiation, and viral proteins that increase the level of VDAC1 expression, with apoptosis being correlated with VDAC1 expression levels ( Shoshan-Barmatz et al, 2010 , 2013 , 2015 , 2020 ; Keinan et al, 2013 ; Shoshan-Barmatz et al, 2017a , b ). Metformin’s anti-cancer effects can be mediated through induction of VDAC1 overexpression, as shown in NCaP cells ( Loubiere et al, 2017 ) in polycystic ovary syndrome-like rats ( Zhang et al, 2017 ) and the presence of citral in RD cells ( Duan et al, 2021 ). VDAC1 overexpression leads to apoptosis induction, as presented in Section “Metformin Modulating Apoptosis: Mitochondria, VDAC1, and HK as Key Factors.”…”

“…The increase in VDAC1 expression levels by metformin ( Loubiere et al, 2017 ; Zhang et al, 2017 ; Duan et al, 2021 ) can explain its pro-apoptotic effect relevant to cancer therapy. However, no clear mechanism is presented to link between metformin ‘s anti-aging activity and VDAC1.…”