Use of herbal medicines and natural products: An alternative approach to overcoming the apoptotic resistance of pancreatic cancer

Lin Li,
Po Sing Leung^,

doi:10.1016/j.biocel.2014.05.021

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Abstract

Pancreatic cancer has a poor prognosis with a 5-year survival rate of <5%. It does not respond well to either chemotherapy or radiotherapy, due partly to apoptotic resistance (AR) of the cancer cells. AR has been attributed to certain genetic abnormalities or defects in apoptotic signaling pathways. In pancreatic cancer, significant mutations of K-ras and p53, constitutive activation of NFκB, over-expression of heat shock proteins (Hsp90, Hsp70), histone deacetylase (HDACs) and the activities of other proteins (COX-2, Nrf2 and bcl-2 family members) are closely linked with resistance to apoptosis and invasion. AR has also been associated with aberrant signaling of MAPK, PI3K–AKT, JAK/STAT, SHH, Notch, and Wnt/β-catenin pathways. Strategies targeting these signaling molecules and pathways provide an alternative for overcoming AR in pancreatic cancer. The use of herbal medicines or natural products (HM/NPs) alone or in combination with conventional anti-cancer agents has been shown to produce beneficial effects through actions upon multiple molecular pathways involved in AR. The current standard first-line chemotherapeutic agents for pancreatic cancer are gemcitabine (Gem) or Gem-containing combinations; however, the efficacy is dissatisfied and this limitation is largely attributed to AR. Meanwhile, emerging data have pointed to a combination of HM/NPs that may augment the sensitivity of pancreatic cancer cells to Gem. Greater understanding of how these compounds affect the molecular mechanisms of apoptosis may propel development of HM/NPs as anti-cancer agents and/or adjuvant therapies forward.

In this review, we give a critical appraisal of the use of HM/NPs alone and in combination with anti-cancer drugs. We also discuss the potential regulatory mechanisms whereby AR is involved in these protective pathways.

Abbreviations

5-FU, 5-fluorouracil;
AR, apoptotic resistance;
ASK1, apoptosis signal-regulating kinase 1;
BD,, bruceine D;
COX-2, cyclooxygenase-2;
EGCG,, epigallocatechin-3-gallate;
EGFR,, epidermal growth factor receptor;
EriB, eriocalyxin B;
ERK,, extracellular signal-regulated kinase;
Gem, gemcitabine;
GnsRh2, ginsenoside Rh2;
GSK3β, glycogen synthase kinase 3β;
HDAC,, histone deacetylase;
HDACIs, histone deacetylase inhibitors;
HM/NP s, herbal medicines and natural products;
Hsp, heat shock proteins;
IL, interleukin;
JAK, Janus-activated kinases;
JNK,, Jun N-terminal kinase;
Keap, Kelch-like ECH-associated protein;
MAPKs,, mitogen-activated protein kinases;
MMP-9, matrix metalloproteinase 9;
Nrf2, nuclear factor erythroid 2-related factor 2;
PI3K, phosphatidylinositol 3-kinase;
ROS,, reactive oxygen species;
SHH,, Sonic hedgehog;
STAT,, signal transducers and activators of transcription;
TRAIL,, tumor necrosis factor-related-apoptosis-inducing-ligand;
VEGF,, vascular endothelial growth factor

Keywords

Bruceine D;
Chinese medicine;
Eriocalyxin B;
Gemcitabine;
Reactive oxygen species

: Corresponding author at: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Room 609A, Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, New Territories, Hong Kong. Tel.: +852 3943 6879; fax: +852 2603 5123.

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