Antimetastatic activity of the photodynamic agent hypericin in the dark

Abstract

A unique property of the photodynamic signal transduction inhibitor hypericin (HY) is high functionality in the dark, which has been shown to result in portfolio of anticancer activities both in vitro and in vivo. Here we show that treatment with HY significantly reduces growth rate of metastases in 2 murine models: breast adenocarcinoma (DA3) and squamous cell carcinoma (SQ2 Cancer is currently viewed as a cell cycle disease. Strategies to treat malignancies are thus shifting from toxic chemotherapy to agents that switch-off positive cell replication transducers specifically or to activators of endogenous negative cell cycle regulators (p53, p21 waf1 , Kip and INK families of proteins). 1 The feasibility of the novel approach is exemplified by recent success in achieving clinical remissions by Imatinib Mesylate (Gleevec), a rationally designed catalytic domain inhibitor of Abl, c-Kit and PDGFR tyrosine kinases. [2][3][4] Other agents such as the cyclin-dependent kinase inhibitors, flavopiridol, 7-hydroxystaurosporine (UCN-01) and staurosporine are at different phases of clinical development. 5,6 Additional attractive targets for intracellular signaling inhibition are modulators of the PKC family of isoenzymes. Perihydroxylated perylene quinones constitute a unique class of photoactivated inhibitors of ser/thr kinases. In this group, hypericin (HY) has been reported to inhibit PKC, 7,8 Erk1/2 kinases and also epidermal growth factor receptor tyrosine kinase. 9 -11 Most of these signaltransduction inhibitory activities of hypericin have been attributed to the photodynamic properties of the compound that were achieved when HY was excited by light at wavelengths absorbed by the molecule. 11 However, recent observations suggest that HY, in addition to its light-dependent anticancer activities, 12 possesses potent anticancer activities and ability to inhibit different signal transduction pathways also in the absence of light activation (dark effects). [13][14][15] We recently demonstrated that the newly identified anti-cancer activities of HY in the dark differ from the well-characterized light-induced effects of the compound in kinetics, modes of tumor cell death and their underling mechanisms. 13 Cell death induction by HY with light occurs rapidly. Within hours after light irradiation, cells undergo apoptosis, or if the light dose is high, also necrosis. In the dark, on the other hand, tumor cell exposure to HY is required for at least 48 hr in order to inhibit cell proliferation. At higher HY concentrations (Ͼ 10 M), the compound killed the tumor cells in the dark via mitotic cell death. 16 Mitotic cell death is a process observed in cancer cells following treatment with different chemotherapeutic agents as well as radiotherapy. The phenomenon is characterized by cells accumulation at G 2 /M, uncoupling of apoptosis, increased cell volume and multinucleation leading to cell death. 17 Although the precise mechanisms leading to mitotic cell death are not fully understood, we have recently identified processes by wh...

In vitro photodynamic therapy of childhood rhabdomyosarcoma

“…These studies revealed impressive anticancer effects regarding tumor growth and anti-angiogenic effects (16,18). Interestingly, hypericin had also anti-metastatic and anti-angiogenic effects in the dark (19,20). Rhabdomyosarcoma is associated with poor survival in advanced tumor stages.…”

Differential regulation of polo-like kinase 1, 2, 3, and 4 gene expression in mammalian cells and tissues

“…Indeed, Plk1 contains a destruction box-like motif and is a substrate of the anaphase-promoting complex/cyclosome, a cell cycleregulated ubiquitin ligase (Kotani et al, 1999;Lindon and Pines, 2004). Intracellular Plk1 levels also appear to be controlled by the molecular chaperone Hsp90, since Plk1 expression levels decrease when cells are treated with compounds that disrupt Plk1:Hsp90 binding (Simizu and Osada, 2000;Blank et al, 2003).…”

Interstitial wires releasing diffusing alpha emitters combined with chemotherapy improved local tumor control and survival in squamous cell carcinoma‐bearing mice

“…Because BALB/c mice bearing SQ2 tumors die primarily from lung metastases, 28 the major increase in life expectancy induced by the combination of 224 Ra-loaded wires and CP indicated that inhibition of the metastatic process may be involved. Thus, we examined the metastatic burden in the lungs from untreated and treated mice and observed that the 224 Ra wires þ CP treatment group attained a significant reduction of 51% in the lung metastatic load compared with the group of inert-treated animals.…”

“…The SQ2 cell line 28 was kindly provided by Dr. Gad Lavie from the Sheba Medical Center, Tel-Hashomer, Israel. This is a murine anaplastic cell line and was generated from an SCC tumor that developed spontaneously in a male BALB/c mouse.…”