Direct effects of non-antifungal agents used in cancer chemotherapy and organ transplantation on the development and virulence of Candida and Aspergillus species

Figures & data

Figure 1 Mammalian targets of cancer chemotherapy agents reported to affect the biology of pathogenic fungi. Arrows represents activation; blocked lines represent inhibition. NFAT_c, nuclear factor of activated T cells; HSP90, heat shock protein 90; HSP70, heat shock protein 70; P, Phosphate group.

Table 1 Direct effects of antineoplastic agents and antibiotics on the growth and virulence of Candida and Aspergillus

		Major effects on Candida spp.			Major effects on Aspergillus spp.
Chemotherapeutic agent		Antifungal activity	Growth and morphogenesis	Virulence trait	Antifungal activity	Growth and morphogenesis	Virulence trait
Conventional cytotoxic agents (nonmetals)
	Alkylating agents (e.g., cyclophosphamide, 5-AC) Antimetabolties (e.g. MTX, 5-FU, ara-C) Vinca alkaloids (e.g., vincristine, vinblastine) Antibiotics (e.g., bleomycin)	Inhibition of Candida spp.: MICs <100–1500 µg/ml; MICs of 5-FU and asparaginase against C. tropicalis, < 1 µg/ml Inhibition of growth in combination with AMB	Inhibition of filamentation, especially in combination with AMB Enhanced formation of pseudomycelia and limitation of macromolecule uptake in C. glabrata (MTX)	Increase in catalase activity in C. albicans (MTX)	No data	Conversion of A. nidulans and A. niger to fluffy phenotype (5-AC) Impaired conidiation in A. fumigatus (5-AC) Increase in mitotic recombination in A. nidulans (5-AC, ara-C)	Increase in elastase activity and angioinvasion of A. fumigatus (5-AC)
Heavy metals
	Cisplatin (cis-diamminedichloroplatinum [II]; see also Hsp90 inhibitors)	Inhibition of C. albicans at ∼40–180 µg/ml); Conflicting in vitro activity data when combined with AMB	Inhibition of C. albicans hyphae and budding Induction of C. albicans mutations, mitotic recombination, and phenotypic switching	Increase in growth, adhesion to HeLa cells, and enolase and proteinase activity in C. albicans		Induced mitotic recombination with A. nidulans
	Arsenic trioxide	No data	No data	No data	No direct effects observed	No direct effects observed	No direct effects observed
	Zinc	No data	No data	No data	Inhibition of mycelial growth	No data	No data
Taxanes
	Docetaxel Paclitaxel Cabazitaxel nab-paclitaxel PG-paclitaxel	No data	No observed effect on actin skeleton in C. albicans (paclitaxel)	No observed effect on endocytosis or phagocytosis in C. albicans (paclitaxel)	No data	No data	No data
Hsp90 inhibitors
	Geldanamycin analogs (17-AAG, 17-DMAG, radicicol, oxime derivatives Purine small-molecule inhibitors Coumarins (novobiocin analogs) Mycograb (antifungal Hsp90) CisPlatin (see above) HDACi (see below)	Increased efficacy of fluconazole in vitro (17-AAG and 17-DMAG) Blocked de novo azole resistance and abrogation of resistance already evolved Blocked resistance to micafungin Reduced paradoxical effect of micafungin and abrogated micafungin-voriconazole antagonism	Induced filamentation of C. albicans	Improved clinical outcomes in invasive candidiasis (recombinant anti-Hsp90 antibody against C. albicans) Combined 17-AAG/17-DMAG and an azole rescued larvae from C. albicans infection	Enhanced activity of caspofungin and voriconazole in A. terreus and A. fumigatus (geldanamycin)	No data	Combined geldanamycin and an echinocandin rescued larvae from A. fumigatus infection
Histone deacytelase inhibitors
	TSA Vorinostat Romidepsin Panobinostat Mocetinostat Entinostat MGCD290	In vitro activity against Candida (MICs 0.15–16 µg/ml; MGCD290) Reduction of trailing and fluconazole MICs (TSA) Decrease in upregulation of CDR1/21 and ERG111 genes In vitro synergy with fluconazole (TSA, uracil-based hydroxamates)	Increase in white-to-opaque cell switching (TSA) Inconsistent inhibition of germ tube formation (TSA) Inhibition of germ-tube formation (vorinostat)	Reduced adherence to pneumocytes (TSA, vorinostat)	In vitro synergy with voriconazole and posaconazole (MGCD290)	Delay in growth and sporulation of A. nidulans Increase in small-molecule production in A. nidulans	No data
DNA topoisomerase II inhibitors
	Anthracyclines Idarubicin Doxorubicin (Adriamycin) Daunorubicin Aclarubicin	In vitro MICs against Candida (50–100 µg/ml; <2 µg/ml for aclarubicin) Inhibition of C. glabrata, and C. albicans (doxorubicin, idarubicin)	Inhibition of hyphal formation in C. Albicans Increase tolerance to AMB at 24 h in C. albicans (doxorubicin) Induces CDR1/CRD21 expression in C. albicans and causes a 4–8 fold increase in MICs to fluconazole (doxorubicin)	Deformation of plasma membrane and mitochondria in Candida utilis (doxorubicin) Disruption of respiration in C. albicans (doxorubicin)	No data	Induction of parameiosis in A. nidulans (doxorubicin)	No data
Bleomycin		In vivo activity against C. albicans	Inhibition of self-splicing Group intron I in C. albicans and subsequent growth	No data	Inhibition of growth A. fumigatus	Arrest of conidial germination, cell wall septation, and hyphal development in A. fumigatus Induction of mitotic recombination, crossing over and mutations in Met-suppressor system in A. nidulans	No data
Fluoroquinolones
	Ciprofloxacin Moxifloxacin Levofloxacin Ofloxacin	In vitro synergy with AMB/L-AMB: (ciprofloxacin, levofloxacin, moxifloxacin) In vitro synergy with caspofungin and voriconazole (ciprofloxacin) In vitro synergy/antagonism with fluconazole (ciprofloxacin, moxifloxacin) Enhancement of fluconazole and AMB in vivo (ciprofloxacin)	No data	Protection of mice from C. albicans pneumonia (moxifloxacin)	Enhancement of in vitro activity of AMB, voriconazole, and caspofungin in A. fumigatus (ciprofloxacin > moxifloxacin)	No data	No data
Tyrosine kinase inhibitors
	Genistein Tyrphostin47 Calphostin C Small-molecule inhibitors: imatinib (dasatinib, nilotinib), erlotinib, and gefinitib	No data	Increase in growth and rate of germination of C. albicans (genistein) Increase in Hsp90 expression (genistein)	Inhibition of endothelial cell endocytosis of C. albicans (genistein) Inhibition of adhesion to endothelial vitronectin in C. albicans (genistein)	No data	Inhibition of uptake of A. fumigatus conidia by macrophages (genistein)	No data
Autophagy inhibitors
	3-MA Wortmannin	No data on direct effects of inhibitors	No data on direct effects of inhibitors	No data on direct effects of inhibitors	Resistance in vitro to wortmannin	No data on direct effects of inhibitors	No data on direct effects of inhibitors

5-AC, 5-azacytidine; 17-AAG, 17-allylamino-17-demethoxygeldanamycin; ara-C, cytosine arabinoside; AMB, amphotericin B; CDR, Candida drug resistant; 17,-DMAG; 17-desmethoxy-17-N,N-diemthylaminoethylaminogeldanamycin; 5FU, 5-fluorouracil; Hsp90, heat shock protein 90; HDACi, histone deacetylase inhibitor; 3-MA, 3-methyladenine; MTX, methotrexate; MIC, minimal inhibitory concentration; PG-paclitaxel, polyglutamate bound paclitaxel; TSA, trichostatin A.

1 CDR1/CDR2 are genes coding for the multidrug efflux transporters of the ATP-binding cassette transporter family; ERG11 is the gene encoding for the enzyme sterol 14α demethylase.

Table 2 Direct effects of corticosteroids and other immunosuppressive agents used in transplantation on the growth and virulence of Candida and Aspergillus spp.

	Major effects on Candida			Major effects on Aspergillus
Drug class	Antifungal activity	Growth and morphogenesis	Virulence	Antifungal activity	Growth and morphogenesis	Virulence
Corticosteroids
Prednisone Methlyprednisolone Hydrocortisone Dexamethasone	Decrease in antifungal effects of nystatin in skin (topical methylprednisolone)	Enhanced germtube formation in serum	Increase in colonization of oral mucosa and gastrointestinal tract of mice by C. albicans and bloodstream translocation Increase in adhesion to epithelial cells (dexamethasone) Enhanced phospholipase and aspartyl proteinase secretion (methylprednisolone)	Increase in growth rates of A. fumigatus and A. flavus (hydrocortisone) Increase in susceptibility to itraconazole but not to amphotericin B (hydrocortisone, prednisone, dexamethasone)	-	-
TOR inhibitors
Rapamycin and analogs 2, 21, 18, and 9	Inhibition of growth in vitro (fungicidal) of C. albicans Demonstration of synergy with AMB and 5-flucytosine in vitro against C. albicans	Inhibition of filamentation in C. albicans	Protection of mice against C. albicans	Inhibition of growth of A. fumigatus, A. flavus, and A. niger Enhancement of azole, caspofungin, and amphotericin B activity in vitro	No data	No data
Calcineurin inhibitors
Cyclosporine and analogs (CsA:211–810)	Demonstration of in vitro and in vivo synergy with azoles and terbinafine against Candida spp., including in biofilm-associated models	Inhibition of germtube formation in C. albicans Inhibition of mycelial transformation of blastospores in C. albicans	Gene deletion studies indicate decreased virulence in systemic and ocular mouse models	Inhibition of growth of A. fumigatus Demonstration of synergistic activity in vitro with azoles and caspofungin	Inhibition of filamentation Reduction of cell wall 1,3-β-glucan synthase activity with caspofungin	No survival advantage in an intravenous mouse model of aspergillosis
Tacrolimus (FK-506) and analogs	Demonstration of in vitro and in vivo synergy with azoles and terbinafine against Candida spp., including in biofilm-associated models	No data	Gene deletion studies indicate decreased virulence in systemic and ocular mouse models	Inhibition of growth of A. fumigatus Synergistic activity in vitro with azoles and caspofungin	Inhibition of hyphal growth and filamentation, and blunting of tips Inhibition of hyphal growth and conidial germination	Conferred survival advantage in an intravenous mouse model of aspergillosis