The synthetic bryostatin analog Merle 23 dissects distinct mechanisms of bryostatin activity in the LNCaP human prostate cancer cell line

Abstract

Bryostatin 1 has attracted considerable attention both as a cancer chemotherapeutic agent and for its unique activity. Although it functions, like phorbol esters, as a potent protein kinase C (PKC) activator, it paradoxically antagonizes many phorbol ester responses in cells. Because of its complex structure, little is known of its structure-function relations. Merle 23 is a synthetic derivative, differing from bryostatin 1 at only four positions. However, in U-937 human leukemia cells, Merle 23 behaves like a phorbol ester and not like bryostatin 1. Here, we characterize the behavior of Merle 23 in the human prostate cancer cell line LNCaP. In this system, bryostatin 1 and phorbol ester have contrasting activities, with the phorbol ester but not bryostatin 1 blocking cell proliferation or tumor necrosis factor alpha secretion, among other responses. We show that Merle 23 displays a highly complex pattern of activity in this system. Depending on the specific biological response or mechanistic change, it was bryostatin-like, phorbol ester-like, intermediate in its behavior, or more effective than either. The pattern of response, moreover, varied depending on the conditions. We conclude that the newly emerging bryostatin derivatives such as Merle 23 provide powerful tools to dissect subsets of bryostatin mechanism and response.

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“…Merle 23 (26, Figure 5), is a synthetic analog of bryostatin and whose structure differs from that of bryostatin 1 (25) in four positions of the space domain fragment. Interestingly, merle 23 (26) showed phorbol ester-like behavior not that of bryostatin in a human prostate cancer cell line (LNCaP), and this finding provided a powerful tool to dissect bryostatins' mechanisms and responses [75,76].…”

“…The final assembly strategy is accomplished by the coupling reaction depicted in Scheme 6 [90,93]. Different methods for the synthesis, to obtain milligram to gram amounts of 31 have been reported [75,93]. Generally, the synthetic pathway of 31 consists of preparation of two fragments, i.e., C-1-C-13 and C-14-C-26, as described by Kishi's group in 1992, and one key fragment (C-27 to C-35).…”

“…Unfortunately, 74 was found to induce tremors or convulsion in mice and other animals [168]. Two derivatives, Ko132 (75) and Ko134 (76), were found to be potent inhibitors of the BCRP-mediated drug efflux in T6400 mouse and T8 human cell lines with low cytotoxicity at an effective concentration of 1 μM [163,169]. In addition, 77 was the most effective inhibitor of BCRP, with very low activity against P-gp or other known drug transporters [168,170].…”

Cross-talks between c-Kit and PKC isoforms in HMC-1560 and HMC-1560,816 cells. Different role of PKCδ in each cellular line

“…Next, PKCd role on apoptosis induced by STI571 was studied by PKCd silencing in HMC-1 560 cell line. The first step was to evaluate PKCd silencing method effectiveness, by using a tested siRNA PKCd [41][42][43][44]. As Fig.…”

Artificial Analogs of Naturally Occurring Tumor Promoters as Biochemical Tools and Therapeutic Leads

“…Recently, the mode of anti-cancer action of Bryo-1 has been investigated intensively using simplified analogs. [105][106][107][108] ATX analog 56, which can be prepared reliably in quantity and tuned for function, should also make a significant contribution to future research aimed at elucidating the anti-cancer mechanism underlying PKC activation.…”