Calein C, a Sesquiterpene Lactone Isolated From Calea Pinnatifida (Asteraceae), Inhibits Mitotic Progression and Induces Apoptosis in MCF-7 Cells

Abstract

Breast cancer is the most common cancer in women worldwide. Estrogen receptor-positive (ER+) breast cancer represents approximately 75% of diagnosed cases, while 15–20% of them are triple-negative (TN). Although there have been improvements in the therapeutic approach, the mortality rate remains elevated. Thus, it is necessary to identify new chemotherapeutic agents. The present study aimed to evaluate the effects of calein C, a sesquiterpene lactone isolated from Calea pinnatifida, on breast cancer cell lines MCF-7 (ER+), Hs578T (TN) and MDA-MB-231 (TN). Calein C significantly reduced the viability of all cell lines; however, MCF-7 cells were more responsive than MDA-MB-231 or Hs578T cells. Thus, the MCF-7 cell line was selected for further investigation. We demonstrated that calein C inhibited cell cycle progression in MCF-7 cells at M-phase. Increased frequency of mitosis was observed in calein C-treated samples compared to the control group, especially of the cell population in initial stages of the mitosis. These events were associated with the ability of calein C to modulate expression levels of critical regulators of mitosis progression. We observed a significant reduction in the relative mRNA abundance of PLK1 and AURKB along with a concomitant increase in CDKN1A (p21) in treated samples. In addition, calein C induced apoptosis in MCF-7 cells due to, at least in part, its ability to reduce the BCL2/BAX ratio. Therefore, our data provide evidence that calein C is an important antimitotic agent and should be considered for further in vivo investigations.

Sesquiterpene Lactones from Calea pinnatifida: Absolute Configuration and Structural Requirements for Antitumor Activity

“…Compound 1 , identified as calein C, was previously isolated from C. urticifolia [ 8 ] and C. zacatechichi [ 9 ]. Our group has also studied this compound previously in order to determine the correct relative position of the acetate and methacrylate groups, by means of HSQC and HMBC NMR in benzene- d 6 ( Table 1 ) [ 18 , 29 ], which were assigned to C-9 and C-8, respectively.…”

“…The literature also reports the cytotoxicity of calein C against the breast cancer cell lines MCF-7, MDA-MB-231 and Hs578T. The data suggest that calein C is able to reduce cell viability as well as inhibit cell cycle progression, consequently resulting in cell death [ 18 ].…”

“…Compound 1, identified as calein C, was previously isolated from C. urticifolia [8] and C. zacatechichi [9]. Our group has also studied this compound previously in order to determine the correct relative position of the acetate and methacrylate groups, by means of HSQC and HMBC NMR in benzene-d6 (Table 1) [18,29], which were assigned to C-9 and C-8, respectively. Once the relative configuration of Compound 1 was unambiguously assigned by NOESY analysis, vibrational circular dichroism (VCD) experiments and calculations were used to determine its absolute stereochemistry for the first time in the literature.…”

“…The literature also reports the cytotoxicity of calein C against the breast cancer cell lines MCF-7, MDA-MB-231 and Hs578T. The data suggest that calein C is able to reduce cell viability as well as inhibit cell cycle progression, consequently resulting in cell death [18]. Similarly to what is observed with calein C, calealactone B was also shown to be cytotoxic against both of the cell lines, whereas the IC 50 values were slightly higher than those obtained for calein C. This difference might be due to the presence of an epoxide in positions C-2 and C-3 instead of the double bond present in calein C.…”

“…In terms of biological potential, literature data suggest that STLs might be responsible for the cytotoxic potential of many species, such as C. pinnatifida [16][17][18] and C. urticifolia [19,20]. Regarding antitumor activity, our research group showed that calein C, an STL isolated from C. pinnatifida, inhibits mitotic progression and induces apoptosis in MCF-7 cell lines by the inhibition of cell cycle progression at the M-phase [18]. Furthermore, analogues of calein C, such as arucanolide, displayed cytotoxicity against melanoma and HL60 cells [17,21].…”