Table 7.

Mechanisms of Resistance to PDT and to Chemotherapy

PDT resistant cells	Chemoresistant cells
Increased cell spreading [7, 44]. Increased cell size and protein content [6, 7].	Increased cell size in samples from patients with chemoresistant SCLC [204].
Increased ploidy in RIF-1 PDT resistant variants [6].	Polyploidization as a mechanism of resistance to chemotherapy, mutagenic drugs and ionizing radiation [279, 280].
Cells transfected with glutathione-associated enzymes protects from PDT-damage [43]. Glutathione content per cell is increased in some PDT resistant cells [6, 7]. SOD2 upregulated after ALA-PDT [92].	Elevatated levels of glutathione-associated enzymes [281]. Elevated GSH synthesis associated with resistance [282]. Overexpression of MnSOD as a mechanism increasing resistance to apoptosis in cancer cells [283].
Increased capacity for viral DNA synthesis was observed in the RIF-8A PDT resistant cells [81].	DNA repair as a resistance mechanism to alkylating agents and other drugs [284, 285], as well as radioresistance [286].
Increased mRNA and expression of several HSPs [6, 43, 174] and GRPs [169].	HSPs and GRPs associated with chemoresistance [287–290].
No demonstrated overexpression of P-gp in PDT resistant cells, but many MDR+ cell lines are cross-resistant to PDT (see Table 4). Subcellular distribution of PS modified in P- gp expressing cells [58].	P-gp associated to MDR resistant tumors [291], correlated to decreased intracellular drug accumulation and subcellular localization [292].
Early response genes and signal transduction pathways activated after PDT [11, 87–90, 293].	Early response genes and signal transduction pathways activated after chemotherapy [294].
Ras transfected cells are resistant to PDT employing ALA [107] and other PS [96].	Ras oncogene involved in chemo and radio resistance [104, 105, 295].
ABCG2 efflux PpIX [67]. Some ABCG2 overexpressing cells are resistant to PDT [51, 72].	ABCG2 effluxes mitoxantrone, camptothecin-derived and indolocarbazole topoisomerase I inhibitors, methotrexate, flavopiridol, and quinazoline ErbB1 inhibitors [65].
RIF-1 PII-PDT resistant cells have smaller mitochondria, produce more ATP, have higher succinate dehydrogenase activity, but diminished membrane potential [44]. A cell line lacking mitDNA was resistant to PDT [41].	The ovarian carcinoma cell C13* cisplatin-resistant variant has similar features [296]. A cell line lacking mitDNA was resistant to DXR but not to alkylating agents [42].
PDT modifies cell adhesion, invasiveness and metastasis [186,189, 190, 197].	Cell adhesion-mediated drug resistance [297]. Increased adhesion to ECM proteins, decreased or increased expression of integrins, increased motility, invasiveness and metastasis [297–299].
Transfection of Bcl-2 confers resistance to PDT [126, 127]. Wild-type p53 transfected cells are more sensitive to PDT [128, 140].	Bcl-2 overexpression related to chemoresistance [300]. Bcl-2 antisense therapy chemosensitizes cells [301]. P53 mutations contribute to resistance to chemo- and radiotherapy [302].
PDT resistant cells show signs of cytoskeleton disorganization [197]. Vimentin confers resistance impairing nuclear apoptosis after PDT [200].	Cytoskeleton alterations are present in MDR cells [303]. Epithelial-mesenchymal conversion involved in invasiveness and metastasis [304]. Vimentin can be considered as a marker of resistance [305]. Caspase cleavage of vimentin promotes apoptosis [306].
Indirect evidence of the role of COX-2 in photoresistance such as combination of PDT with COX-2 inhibitors, resulting in enhanced photodamage [26, 211, 214].	COX-2 is associated by resistance to standard cancer treatment [210].
Bhowmick [231] et al. reported evidence for increased tumor cell resistance due to iNOS upregulation in a PDT model.	NO involved in resistance to radiotherapy [219]. Blocking NOS reverses apoptosis [222].
PDT-induced tissue hypoxia as a result of vascular damage and photochemical oxygen consumption limit its efficacy [240]. PDT induce stabilization of (HIF1)-alpha [131, 241].	Hypoxia reduces the effectiveness of radiotherapy and some O2-dependent cytotoxic agents [240].
Survivin was found to be target for PDT, but there are still no reports on upregulation in PDT resistant cells [236, 239, 238].	In various tumors, highsurvivin levels are correlated with poor prognosis, decreased apoptosis, increased angiogenesis, and chemoresistance in cancercells [233, 234].