Resistance to cisplatin (CDDP) is a major cause of cancer treatment failure, including human breast cancer. The tumor suppressor protein p53 is a key factor in the induction of cell cycle arrest, DNA repair, and apoptosis in response to cellular stimuli. This protein is phosphorylated in serine 15 and serine 20 during DNA damage repair or in serine 46 to induce apoptosis. Resveratrol (Resv) is a natural compound representing a promising chemosensitizer for cancer treatment that has been shown to sensitize tumor cells through upregulation and phosphorylation of p53 and inhibition of RAD51. We developed a CDDP-resistant MCF-7 cell line variant (MCF-7_R) to investigate the effect of Resv in vitro in combination with CDDP over the role of p53 in overcoming CDDP resistance in MCF-7_R cells. We have shown that Resv induces sensitivity to CDDP in MCF-7 and MCF-7_R cells and that the downregulation of p53 protein expression and inhibition of p53 protein activity enhances resistance to CDDP in both cell lines. On the other hand, we found that Resv induces serine 20 (S20) phosphorylation in chemoresistant cells to activate p53 target genes such as PUMA and BAX, restoring apoptosis. It also changed the ratio between BCL-2 and BAX, where BCL-2 protein expression was decreased and at the same time BAX protein was increased. Interestingly, Resv attenuates CDDP-induced p53 phosphorylation in serine 15 (S15) and serine 46 (S46) probably through dephosphorylation and deactivation of ATM. It also activates different kinases, such as CK1, CHK2, and AMPK to induce phosphorylation of p53 in S20, suggesting a novel mechanism of p53 activation and chemosensitization to CDDP.

We analyze the effect of chronic undernourishment on extensor digitorum longus (EDL) muscle maturation in the rat. Cytochrome c oxidase (COX) and alkaline ATPase histoenzymatic techniques were used to determine the relative proportion of different fiber types (oxidative/glycolytic and type I, IIa/IId, or IIb, respectively) and their cross-sectional area in control and undernourished EDL muscles at several postnatal (PN) ages. From PN days 15 to 45, undernourished EDL muscles showed predominance of oxidative and type IIa/IId fibers, but from PN days 60 to 90, there were a larger proportion of oxidative fibers and an equal proportion of type IIa/IId and IIb fibers. Meanwhile, in adult stages (from PN days 130–365), the relative proportion of fiber types in control and undernourished EDL muscles showed no significant differences. In addition, from PN days 15 to 90, there was a significant reduction in the cross-sectional area of all fibers (slow: 13–53%; intermediate: 24–74%; fast: 9–80%) but no differences from PN days 130 to 365. It is suggested that chronic undernourishment affects the maturation of fast-type muscle fibers only at juvenile stages (from PN days 15–45) and the probable occurrence of adaptive mechanisms in muscle fibers, allowing adult rats to counterbalance the alterations provoked by chronic food deprivation.

Resistance to HER2 tyrosine-kinase inhibitor Lapatinib (Lap) is one of the leading causes of cancer treatment failure in HER2+ breast cancer (BC), associated with an aggressive tumor phenotype. Cryptotanshinone (Cry) is a natural terpene molecule that could function as a chemosensitizer by disturbing estrogen receptor (ERα) signaling and inhibiting the protein translation factor-4A, eIF4A. Therefore, we evaluated Cry dual regulation on eIF4A and ERα. This study aimed to elucidate the underlying mechanisms of Lap chemoresistance and the impact of Cry on them. We generated two Lap-resistant BT474 cell HER2+ variants named BT474^LapRV1 and BT474^LapRV2 with high chemoresistance levels, with 7- and 11-fold increases in EC₅₀, respectively, compared to BT474 parental cells. We found a PDCD4-p70S6Kβ axis association with Lap chemoresistance. However, a concomitant down-regulation of the RAF-MEK-ERK cell survival pathway and NF-κB was found in the chemoresistant cell variants; this phenomenon was exacerbated by joint treatment of Cry and Lap under a Lap plasmatic reported concentration. Optimized calcium management was identified as a compensatory mechanism contributing to chemoresistance, as determined by the higher expression of calcium pumps PMCA1/4 and SERCA2. Contrary to expectations, a combination of Lap and Cry did not affect the chemoresistance despite the ERα down-regulation; Cry-eIF4A binding possibly dampens this condition. Results indicated the pro-survival eIF4A/STAT/Bcl-xl pathway and that the down-regulation of the MAPK-NF-κB might function as an adaptive mechanism; this response may be compensated by calcium homeostasis in chemoresistance, highlighting new adaptations in HER2+ cells that lead to chemoresistance.