Investigating the Anticancer Potential of Salvicine as a Modulator of Topoisomerase II and ROS Signaling Cascade

Abstract

Salvicine is a new diterpenoid quinone substance from a natural source, specifically in a Chinese herb. It has powerful growth-controlling abilities against a broad range of human cancer cells in both in vitro and in vivo environments. A significant inhibitory effect of salvicine on multidrug-resistant (MDR) cells has also been discovered. Several research studies have examined the activities of salvicine on topoisomerase II (Topo II) by inducing reactive oxygen species (ROS) signaling. As opposed to the well-known Topo II toxin etoposide, salvicine mostly decreases the catalytic activity with a negligible DNA breakage effect, as revealed by several enzymatic experiments. Interestingly, salvicine dramatically reduces lung metastatic formation in the MDA-MB-435 orthotopic lung cancer cell line. Recent investigations have established that salvicine is a new non-intercalative Topo II toxin by interacting with the ATPase domains, increasing DNA-Topo II interaction, and suppressing DNA relegation and ATP hydrolysis. In addition, investigations have revealed that salvicine-induced ROS play a critical role in the anticancer-mediated signaling pathway, involving Topo II suppression, DNA damage, overcoming multidrug resistance, and tumor cell adhesion suppression, among other things. In the current study, we demonstrate the role of salvicine in regulating the ROS signaling pathway and the DNA damage response (DDR) in suppressing the progression of cancer cells. We depict the mechanism of action of salvicine in suppressing the DNA-Topo II complex through ROS induction along with a brief discussion of the anticancer perspective of salvicine.

Keywords: DNA damage response (DDR); ROS signaling; anticancer properties; diterpenoid quinone; multidrug-resistant (MDR); topoisomerase II.

Figure 1

Induction of DNA damage response (DDR) by reactive oxygen species (ROS) signaling in cancer tissue. ROS signaling pathways can effectively induce the DDR in cancer tissue. Small non-coding RNA (snc-RNA) positive regulators play important roles in DDR activation. DDR activation effectively modulates the cell cycle checkpoint, transcriptional program, DNA repair pathways, and programmed cell death.

Figure 2

Schematic illustration of the detection of reactive oxygen species (ROS)-mediated DNA damage with DNA repair.

Figure 3

Schematic representation of reactive oxygen species (ROS)-mediated DNA damage response (DDR). Shown is a significant strategy in which the altered development of ROS increases the sources of endogenous DNA damage in various cancers, such as myeloid malignancies. In chronic myeloid leukemia (CML), the fusion gene BCR–ABL produces ROS, as do FLT3/ITD mutations in acute myeloid leukemia (AML) and RAS mutations in myelodysplastic syndromes (MDS)/myeloproliferative diseases (MPDs). Increased ROS can cause a sequence of genomic instabilities by Akt and NADPH oxidases, resulting in DNA double-strand breaks (DSBs) and altered repair, further leading to the acquisition of genomic modifications. There is accumulating evidence that defects in the primary signaling pathways for DSBs, non-homologous end-joining (NHEJ), and activation of the RAS/PI3K/STAT signaling pathways result in the increased expression of complementary or “backup” recovery, which can result in chromosomal deletions and translocations.

Figure 4

An estimated signaling pathway exhibiting the mechanisms of action of salvicine in inhibiting topoisomerase II and inducing DNA damage. All of these activities are regulated by ROS generation. Here, the positive sign represents stimulation or enhancement and the negative sign represents inhibition.

Figure 5

Salvicine-mediated anti-proliferative and/or anticancer effect pathway. As an initial step, salvicine produces reactive oxygen species (ROS) and binds to the double-strand (DS)-DNA moiety, the cysteine residue (a). At the same time, it enables disruption of the double-strand DNA (b), additionally inhibiting the rapidly proliferating cells, including cancerous cells. Salvicine directly interacts with the DNA-dependent protein kinase enzyme (DDPKE) (c), which is why the inactive enzyme functions with the inhibition of cellular growth (d), halting the rapidly propagating cancerous cells. On the contrary, the c-myc protein plays a key regulatory role during DS-DNA growth, but it directly binds with the promoter region of the c-myc gene (e) and interestingly yields a malfunction enzyme (f), which damages the DS-DNA (g) and subsequently downregulates metastasis. However, telomere repeat binding factor-2 is synthesized by the trf2 gene that plays a fundamental role in normal cells, and salvicine binds to the trf2 gene (h) and shuts down the expression of the telomerase protein (i) that induces apoptosis (j), which mediates the anticancer effect. Finally, salvicine disrupts the cell–extracellular matrix adhesion protein, mainly integrin β1 (k), which is involved in cell cycle arrest (l) and hinders neoangiogenesis (m) and even cancer metastasis.

Figure 6

Cellular signaling pathways involved in salvicine-induced anticancer potential via the p38 MAPK and c-Jun N-terminal kinase (JNK) cascades.