Bisphosphonates Inhibit Stellate Cell Activity and Enhance Antitumor Effects of Nanoparticle Albumin–Bound Paclitaxel in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic stellate cells (PSCs) have been recognized as the principal cells responsible for the production of fibrosis in PDAC. Recently PSCs have been noted to share characteristics with cells of monocyte-macrophage lineage (MML cells). Thus, we tested whether PSCs could be targeted with the nitrogen-containing bisphosphonates (NBPs) [pamidronate (Pam) or zoledronic acid (ZA)], which are potent MML cell inhibitors. In addition, we tested NBPs treatment combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to enhance antitumor activity. In vitro we observed that PSCs possess α-naphthyl butyrate esterase (ANBE) enzyme activity, a specific marker of MML cells. Moreover NBPs inhibited PSCs proliferation, activation, release of macrophage chemoattractant protein-1 (MCP-1) and type I collagen expression. NBPs also induced PSC apoptosis and cell cycle arrest in the G1 phase. In vivo, NBPs inactivated PSCs; reduced fibrosis; inhibited tumor volume, tumor weight, peritoneal dissemination, angiogenesis, and cell proliferation; and increased apoptosis in an orthotopic murine model of PDAC. These in vivo antitumor effects were enhanced when NBPs were combined with nab-paclitaxel but not gemcitabine (Gem). Our study suggests that targeting PSCs and tumor cells with NBPs in combination with nab-paclitaxel may be a novel therapeutic approach to PDAC.

Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer

“…The immunohistochemical analysis was perfomed as previously described (19). Briefly, unstained sections of mouse tissues were deparaffinized and rehydrated.…”

“…A single microvessel was defined as a discrete cluster or single cell stained positive for CD31, and the presence of a lumen was required for scoring as a microvessel (20). Cell apoptosis was determined by immunohistochemical analysis as described previously (19). …”

Pancreatic stellate cells: A dynamic player of the intercellular communication in pancreatic cancer

“…Candidates include the Sonic hedgehog (Shh) inhibitor [43], albumin-bound paclitaxel [44], all trans retinoic acid [45], a PEGylated form of human recombinant PH20 hyaluronidase [46], and bisphosphonates [47]. In general, these candidates reduce the stroma and tumor volume, increased vascularity and improved drug delivery in tumors.…”

Scientific rationale for integrative and personalised strategies for pancreatic ductal adenocarcinoma management

“…Similarly, use of biphosphonates targeting PSCs caused a reduction in fibrosis, tumour volume/ weight, peritoneal dissemination, angiogenesis and cell proliferation and increased apoptosis in an murine PDAC model [235]. These in vivo anti-tumour effects were enhanced when biphosphonates were combined with nab-paclitaxel [235]. Surprisingly, while PSCs-released HGF inhibition was effective in inhibiting local tumour growth, tumour angiogenesis and metastasis, anti-metastatic effect of HGF inhibition was lost when combined with gemcitabine [236].…”

“…Nab-paclitaxel also decreases the content of PSCs, leading to reduced tumour stiffness [234]. Similarly, use of biphosphonates targeting PSCs caused a reduction in fibrosis, tumour volume/ weight, peritoneal dissemination, angiogenesis and cell proliferation and increased apoptosis in an murine PDAC model [235]. These in vivo anti-tumour effects were enhanced when biphosphonates were combined with nab-paclitaxel [235].…”