Table 1.

PROSTATE CANCER RADIOSENSITIZERS TOWARDS INDIVIDUAL RADIORESISTANCE CONDITIONS.

Gene aberration-related radioresistance	Customized radiosensitizers
Cancer cell growth pathway hyperactivation:
- Phosphatidyl inositol 3-kinase(PI3K) -Akt/mammalian target of rapamicin (mTOR) pathway.	- NVP-BEZ 235 or NU7 441, as dual ATP-competitive PI3K and mTOR blockers. NVP-BEZ also inhibits HIF-1. Zotarolimus, as analogue of rapamicin, blocks mTOR.
- Janus tyrosine kinase - Signal transducer activator of transcription (Jak-STAT) pathway.	- AG 490, as a suitable specific blocker of Jak-STAT pathway, can radiosensitize the prostate cancer cells. Ruxolitinib and fludarabine are respectively selective inhibitors of Jak1/2 and STAT3.
- Interactions between overexpressed MDM2 (mouse double minute 2) and p53 with subsequent lack of p53 normal function, hence enhancement of cancer cell growth.	- Nutlins, as cis-imidazoline analogs, may prevent p53-MDM2 interactions, so inhibiting cancer cells growth meanwhile restoring tumor radiosensitivity. MDM2 antagonist Nutlin-3 also facilitates apoptosis.
- Overexpression of HER2(Human epidermal growth factor receptor type2 of tyrosine kinase).	- Trastuzumab (Herceptin), by blocking HER2, inhibits PCa cell proliferation.
- Histone deacetylase (HDAC) epigenetic hyperactivity.	- SB939, as PCa cell HDAC inhibitor
Cancer cell apoptotic pathway evasion:
- Suppression of apoptosis machinery by overexpression of antiapoptotic Bcl-2 gene.	- HA14-1 and ABT-263(Navitoclax), as inhibitors of Bcl-2, facilitate the apoptotic process.
- Suppression of proteolytic cleavage of poly(ADP-ribose) polymerase-1 (PARP-1), so preventing apoptosis-proper DNA fragmentation.	- Olaparib, veliparib, niraparib, as blockers of PARP-1, allow the cancer cell death, so it reaching the prostate cancer cell radiosensitization.
- Survivin gene overexpression, by interfering with caspase activity, supports cancer cell survival.	- YM155, as survivin inhibitor, acts as radiosensitizer of prostate cancer cells.
- Clusterin, as inhibitor of Bax proapoptotic activity, protects cancer cells from TGFβ-induced apoptotic mechanisms.	- OGX-011 antisense nucleotide, by promoting a down regulation of clusterin expression, can restore cancer cell apoptosis and radiosensitivity.
- Ceramide accumulation-induced, by feed-back, ceramidase gene up-regulation leads, in turn, to produce the ceramide catabolite sphingosine and its phosphorilated derivative sphingosine-1-phosphate, that may support activation of Akt pathway, with following cancer cell growth enhancement and radioresistance onset.	- LCL 521/385, as promoters of ceramidase proteolytic degradation, can mantain the ceramide-associated apoptotic process meanwhile radiosensitizing cancer cells. -Toremifene, as tamoxifen-like antiestrogen, is also an efficacious inhibitor of acid ceramidase activity.
In addition, some inhibitors of cytoskeletal signaling pathway, such as Akt blocker perifosine as well as both paclitaxel and epothilone B microtubule stabilizers, can accelerate the development of the cell apoptotic process.
Cancer stem cell-related radioresistance:
- Particular gene mutation-dependent over-activation of stem cell specific pathways – such Wnt/βcatenin-, Hedgehog-and Notch signaling pathways – plays an important role in facilitating both self-renewal process and radioresistance onset.	- Perifosine, besides blocking Akt and PI3K, can also inhibit the Wnt signaling, with following restoration of tumor radiation sensitivity. Miltefosine, though like perifosine, isn’t suitable as a radiosensitizer agent.
- CXCR4 (chemochine CXC of receptor 4), by interacting with its ligand CXCL12, can cause both cancer stem cell chemo- and radioresistance.	- Foreseeable block of CXCR4–CXCL12 interactions should represent a promising opportunity to refine the prostate cancer radiation therapy.