Table 1.

Summary of combination therapies and their mechanism in regulation gemcitabine resistance.

Pathway	Target	Compound	Mechanism of action
Hh	Smo	Vismodegib, LDE225	Phase II trials of vismodegib and Phase I trials of LDE225 in combination with gemcitabine are ongoing (http://www.clinicaltrials.gov/).
		Chloroquine	Chloroquine treatment in combination with gemcitabine significantly decreased CSCs, via inhibition of hedgehog signaling in the stroma.47
	Gli1	Perifosine	Perifosine, an Akt inhibitor, through suppressing Gli1 activation, can enhance gemcitabine-induced cytotoxicity in pancreatic cancer cells33
		Lithium	By inhibiting the activity of glycogen synthase kinase 3β (GSK3β), therefore promoting the ubiquitin-dependent proteasome degradation of Gli1.34
	SHH	Arsenic trioxide (ATO)	Combination treatment of ATO and low dose gemcitabine inhibits tumor growth, decreases the expression of CD24, CD44, and aldehyde dehydrogenase 1 family member A1 significantly in mouse model.48
Wnt	β-Catenin	PG545	PG545 in combination with gemcitabine exerts anti-tumor activity by disrupting Wnt/β-Catenin signaling.55
		Masitinib	Masitinib, a tyrosine kinase inhibitor, can sensitize gemcitabine treatment through down-regulation Wnt/β-Catenin signaling pathway.56
Notch	γ-secretase	DAPT, MRK003	DAPT and MRK003 effectively inhibit intratumoral Notch signaling in PDA, leading to a remarkable decrease in chemosensitivity to gemcitabine67, 68
		L1790	L1790 are shown to reverse the gemcitabine resistance induced by PSCs.72
	DLL4	Neutralizing antibodies	Neutralizing antibodies against human DLL4 reduces the percentage of CSC in gemcitabine-resistant mouse model.73
	Notch-1	Sulforaphane (SF)	Through down-regulation of Notch-1, Sulforaphane (SF) prevented gemcitabine-induced selection of ALDH1 positive cells74